TABLE 3.
ACMG classification of rare variants in the SLC26A4 gene
| No. | Variants | Patients | Reference | Classification | |||
|---|---|---|---|---|---|---|---|
| ClinVar | DVDa | ACMG | ACMG criteria | ||||
| 1 |
c.87G>C p.Glu29Asp |
1 | NI | P | LP |
PM2: Not found in gnomAD PM3: Pathogenic mutation confirmed in trans in one patient PM5: Another pathogenic missense variant (c.85G>C, p.Glu29Gln) at the same codon PP4: Patient phenotype highly specific for gene |
|
| 2 |
c.349del Frameshift |
2 | Pang, Chai, Chen, et al. (2015), Pang, Chai, He, et al. (2015), Wang et al. (2007), Zhao et al. (2014) | P | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2_Supporting: gnomAD exome East Asian allele frequency = 0.000461 <0.0007 PM3_Strong: Pathogenic mutation confirmed in trans in one patient and phase unknown in four patients PP4: Patient's phenotype highly specific for gene |
| 3 |
c.589G>A p.Gly197Arg |
3, 4, 5 | Liu, Wang, et al. (2016), Zhao et al. (2014) | P | P | P |
PM2: gnomAD exome East Asian allele frequency = 0.00005437 <0.00007 PM3_VreyStrong: Pathogenic mutation confirmed in trans in one patient and phase unknown in seventeen patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 4 |
c.1586T>G p.Ile529Ser |
6 | Gao et al. (2016), Huang et al. (2011), Qi Li and Yuan (2012), Zhao et al. (2014) | P/LP | P | P |
PM2: Not found in gnomAD PM3_VreyStrong: Pathogenic mutation phase unknown in eight patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 5 |
c.1786C>T Stop‐gain |
6 | Liu, Wang, et al. (2016) | NI | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: Not found in gnomAD PM3: Pathogenic mutation confirmed in trans in one patient PP4: Patient's phenotype highly specific for gene |
| 6 |
c.317C>A p.Ala106Asp |
7, 8‐1, 8‐2 | Campbell (2001) | NI | P | P |
PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in 3 patients and phase unknown in two patients PP1: Segregation in one affected relative PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 7 |
c.2167C>G p.His723Asp |
9 | Yao et al. (2015), Yuan et al. (2009), Zhao et al. (2014) | NI | P | P |
PM2: gnomAD genomes East Asian allele frequency = 0.00005437 <0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in two patients and phase unknown in four patients PM5: Another missense pathogenic variant (c.2168A>G, p.His723Arg) at the same codon PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 8 |
c.946G>T Stop‐gain |
10, 11 | Gao et al. (2016), Huang (2011), Zhao et al. (2014) | P | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in two patients and phase unknown in six patients PP4: Patient's phenotype highly specific for gene |
| 9 |
c.2174_2177 dup Frameshift |
12 | Chai et al. (2013), Yao, Li, et al. (2013) | P | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: gnomAD genomes East Asian allele frequency = 0.000007959 <0.00007 PM3_Strong: Pathogenic mutation confirmed in trans in one patient and phase unknown in two patients PP4: Patient's phenotype highly specific for gene |
| 10 |
c.281C>T p.Thr94Ile |
13 | Zhao et al. (2014) | P | P | P |
PM2: gnomAD genomes East Asian allele frequency = 0.00005437 <0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in two patients and phase unknown in six patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 11 |
c.1318A>T Stop‐gain |
14, 15 | (Zhao et al., 2014) | P | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in two patients and phase unknown in four patients PP4: Patient's phenotype highly specific for gene |
| 12 |
c.916dup Frameshift |
16‐1, 16‐2 |
Gao et al. (2016), Han et al. (2017), Jiang et al. (2015, 2017) |
P/LP | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2_Supporting: gnomAD East Asian allele frequency = 0.0001631 <0.00007 PM3_Strong: Pathogenic mutation in six patients phase unknown PP1: Segregation in one affected relative PP4: Patient's phenotype highly specific for gene |
| 13 |
c.1656T>G p.Ser552Arg |
16‐1, 16‐2 | Chen et al. (2016) | NI | NI | LP |
PM2: Not found in gnomAD PM3_Strong: Pathogenic mutation confirmed in trans in two patients and phase unknown in one patient PP1: Segregation in one affected relative PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 14 |
c.2162C>A p.Thr721Lys |
17 | NI | NI | LP |
PM2: Not found in gnomAD PM3: Pathogenic mutation phase known in one patient PM5: Another pathogenic missense variant (c.2162C>T, p. Thr721Met) at the same codon PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
|
| 15 |
c.109G>T Stop‐gain |
18 | Yuan et al. (2009), Zhao et al. (2014) | P | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: Not found in gnomAD PM3_Strong: Pathogenic mutation confirmed in trans in one patient and phase unknown in two patients PP4: Patient's phenotype highly specific for gene |
| 16 |
c.439A>G p.Met147Val |
19, 30‐1, 30‐2 | Hosoya et al. (2019), Huang (2011), Lee et al. (2015), Tsukamoto et al. (2003), Zhao et al. (2014) | A | P | P |
PP1: Segregation in one affected relative PM2_Supporting: gnomAD East Asian allele frequency = 0.0001087 <0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in three patients and phase unknown in six patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 17 |
c.387del Frameshift |
20 | Wang et al. (2007), Zhao et al. (2014) | NI | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: Not found in gnomAD PM3_Strong: Pathogenic mutation confirmed in trans in one patient and phase unknown in two patients PP4: Patient's phenotype highly specific for gene |
| 18 |
c.1336C>T Stop‐gain |
21, 22, 23 | Zhao et al. (2014) | P/LP | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: gnomAD exome allele frequency = 0.000007089 <0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in three patients and phase unknown in six patients PP4: Patient's phenotype highly specific for gene |
| 19 |
c.1343C>T p.Ser448Leu |
22 | Gao et al. (2016), Chen and Liu (2014), Lai et al. (2007), Liu, Wang, et al. (2016), Liu, Wu, et al. (2016), Wu et al. (2008), | LP | P | P |
PM2_Supporting: gnomAD genomes East Asian allele frequency = 0.0001088 <0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in two patients and phase unknown in 10 patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 20 |
c.2000T>C p.Phe667Ser |
24 | Chen et al. (2012), Chen and Liu (2014), Leilei Zhao et al. (2018), Liu, Wang, et al. (2016), Zhao et al. (2014) | NI | P | P |
PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in three patients and phase unknown in five patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 21 |
c.1547dup Frameshift |
25 | Chen and Liu (2014), Gao et al. (2016), Liu, Wang, et al. (2016), Zhang et al. (2016) | LP | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2_Supporting: gnomAD East Asian allele frequency = 0.000272 <0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in two patients and phase unknown in five patients PP4: Patient's phenotype highly specific for gene |
| 22 |
c.1264‐12T>A aberrant splicing |
25 | Wu et al. (2016) | NI | P | P |
PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in one patient and phase unknown in seven patients PP4: Patient's phenotype highly specific for gene |
| 23 |
c.754T>C p.Ser252Pro |
26 | Duan et al. (2017), Liu, Wang, et al. (2016) | NI | P | P |
PM2: gnomAD genomes East Asian allele frequency = 0.00005437 <0.00007 PM3_VeryStrong: Pathogenic mutation confirmed in trans in five patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 24 |
c.415+2T>C aberrant splicing |
27 | Zhao et al. (2014) | NI | LP | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in one patient and phase unknown in six patients PP4: Patient's phenotype highly specific for gene |
| 25 |
c.1746del Frameshift |
28 | Wang et al. (2007), Yao, Chen, et al. (2013), Yao, Li, et al. (2013), Zhao et al. (2014) | P | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in four patients and phase unknown in one patient PP4: Patient's phenotype highly specific for gene |
| 26 |
c.1667A>G p.Tyr556Cys |
29 | Lopez‐Bigas et al. (2002), Wang et al. (2017) | P/LP | P | P |
PM2: gnomAD genomes allele frequency = 0.00001594 <0.00007 PM3_Strong: Homozygous confirmed in trans in four patients and pathogenic mutation phase unknown in one patient PP1_Strong: Segregation in three affected relatives and one unaffected relative PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 27 |
c.697G>C p.Val233Leu |
29 | Hu et al. (2007), Huang et al. (2018) | VUS | P | LP |
GnomAD genomes East Asian allele frequency = 0.001353 >0.0007, not apply to PM2 PM3_Strong: Pathogenic mutation confirmed in trans in one patient and phase unknown in 4 patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 28 |
c.1173C>A p.Ser391Arg |
31 | Gao et al. (2016), Huang et al. (2011), Liu, Wang, et al. (2016), Zhao et al. (2014) | LP | P | P |
PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in one patient and phase unknown in six patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 29 |
c.1991C>T p.Ala664Val |
32 | Han et al. (2017), Huang et al. (2011), Zhao et al. (2014) | NI | P | P |
PM2: Not found in gnomAD PM3_VeryStrong: Pathogenic mutation confirmed in trans in one patient and phase unknown in six patients PP3: REVEL score >0.7 PP4: Patient's phenotype highly specific for gene |
| 30 |
c.1299dup Frameshift |
33‐1, 33‐2 | NI | P | P |
PVS1: Null variant in the gene with established LOF as a disease mechanism PP1: Segregation in one affected relative PM2: Not found in gnomAD PM3_Strong: Pathogenic mutation phase known in two patients PP4: Patient's phenotype highly specific for gene |
|
Variants are based on SLC26A4 canonical transcript NM_000441.2.
Deafness variation database.