TABLE 1.
Novel variants discovered by the HEar-Seq gene panel in Israeli Jewish families with hearing loss
| Gene | Family | Inheritance* | Ethnicity** | Genomic coordinates (hg19) |
cDNA | Variant type | Effect | Allele freq controls of same ethnicity^ |
Allele freq in unrelated deaf^^ |
ClinVar ID |
ACMG classification (criteria)*** |
|---|---|---|---|---|---|---|---|---|---|---|---|
| ATOH1 NM_005172.1 | HL263 | AD | M | chr4:94751102 | c.1030delC | Indel | His344fs17Ter | 0 | 0 | 813817 | P (PM2, PM4, PP1_S, PP3, PP4) |
| ATP2B2 NM_001001331.2 | DF328 | AD | A | chr3:10420936 | c.1033C>T | Nonsense | Gln345Ter | 0 | 0 | 1337668 | P (PM2, PM4, PP1_S, PP3, PP4) |
| CABP2 NM_001318496.1 | DF326 | AR | Mixed | chr11:67289435 | c.250G>A | Missense | Glu84Lys | 0 | 0 | 1337669 | P (PM2, PM3_S, PP1_M, PP3, PP4) |
| CEACAM16 NM_001039213.3 | DF301 | AR | M | chr19:45208901 Founder allele | c.703C>T | Missense | Arg235Cys | 0 | 0.008 | 236048 | P (PS4, PM2, PP1_S, PP3, PP4) |
| CLPP NM_006012.2 | DF313 | AR | S A |
chr19:6361758 chr19:6361914 |
c.173T>G (mat) c.233G>C (pat) |
Missense Missense |
Leu58Arg Arg78Pro |
0.004 0 |
0 0 |
500291 813818 |
1) LP (PM2, PM3_P, PP1_M, PP3, PP4) 2) LP (PM2, PM3_P, PP1_M, PP3, PP4) |
| COCH NM_004086.2 | HL1103 | AD | A | chr14:31355200 | c.1159C>T | Missense | Leu387Phe | 0 | 0 | 236036 | LP (PM2, PP1_M, PP3, PP4) |
| COL11A2 NM_080680.2 | HL1140 | AR | S M |
chr6:33152074 chr6:33138676 |
c.967insC c.3385G >A |
Indel Missense |
Thr323fs17Ter Gly1129Arg |
0 0 |
0 0 |
813820 813821 |
1) P (PVS1, PM2, PM3_P, PP1_M) 2) P (PM2, PM3_S, PP1_M, PP3, PP4) |
| EYA4 NM_172105.3 | HL21 | AD | Mixed | chr6:133783474 | c.441delC | Indel | Tyr148fs49Ter | 0 | 0 | 236032 | P (PVS1, PM2, PM4, PP1, PP3, PP4) |
| EYA4 NM_172105.3 | DF312 | AD | M | chr6:133844297 - 133844299 | c.1720_1722 delTACinsAAA | 2 bp changes in same codon | Tyr574Lys | 0 | 0 | 1164280 | LP (PM2, PM2, PP1, PP3, PP4) |
| GATA3 NM_002051.2 | HL738 | AD | A | chr10:8100707 | c.681ins35 | Indel | Glu228fs37Ter | 0 | 0 | 236031 | P (PVS1, PM2, PP1_M, PP3, PP4) |
| GATA3 NM_002051.2 | HL769 | AD | Mixed | chr10:8106009 | c.829G>A | Missense | Asp277Asn | 0 | 0 | 813823 | LP (PM2, PP1_S, PP3) |
| MITF NM_198159.2 | DF311 | AD | S | chr3:70001035 | c.935T>C | Missense | Leu312Pro | 0 | 0 | 547531 | P (PS4_P, PM2, PP1, PP3, PP4) |
| MITF NM_198159.2 | DF186 | AD | S | chr3:70014025 | c.1190delG | Indel | Gly397fs15Ter | 0 | 0 | 236050 | P (PVS1, PM2, PP1, PP3, PP4) |
| MITF NM_198159.2 | DF219 | AD | A | chr3:70005649 | c.981InsC | Indel | Leu327fs9Ter | 0 | 0 | 813825 | P (PVS1, PM2, PM4, PP1, PP3, PP4) |
| MYO6 NM_004999.3 | DF305 | AD | A | chr6:76538307 | c.238C>T | Nonsense | Arg80Ter | 0 | 0 | 178957 | P (PVS1, PM2, PP1, PP3, PP4) |
| MYO6 NM_004999.3 | HL1133 | AD | S | chr6:76568683 | c.1452insT | Nonsense | Asn485Ter | 0 | 0 | 1337671 | P (PVS1, PM2, PM4, PP1_M, PP3, PP4) |
| MYO6 NM_004999.3 | HL1274 | AD | A | chr6:76568710 | c.1473del3insC | Indel | skip exon 14, Glu461fs13Ter | 0 | 0 | 236034 | P (PVS1, PM2, PM4, PP1, PP3) |
| MYO6 NM_004999.3 | HL158 | AD | A | chr6:76624636 | c.3765delC | Indel | Cys1256fs28Ter | 0 | 0 | 813826 | P (PVS1, PM2, PM4, PP1, PP3, PP4) |
| MYO15A NM_016239.3 | HL72 | AR | M | chr17:18054799 | c.7751_8224del 3446ins23 | CNV | Gln2583fs19Ter | 0 | 0.003 | 236039 | P (PVS1, PM2, PM4, PP1, PP3, PP4) |
| MYO15A NM_016239.3 | DF327 DF317 |
AR | A | chr17:18069748 Founder allele |
c.9861C>T | Silent | Gly3287Gly | 0 | 0.003 | 228276/45777 | P (PM2_P, PM3_S, PP1_S, PP3) |
| PCDH15 NM_001142769.1 | HL1134 | AR | M | chr10:56287598 | c.146T>C | Missense | Val49Ala | 0 | 0.003 | 450626 | LP (PM2, PM3_P, PP1, PP3, PP4) |
| SLC26A4 NM_000441.1 | HL1132 HL1327 |
AR | A | chr7:107312627 | c.349C>T | Missense | Leu117Phe | 0.007 | 0.013 | 43555 | P (PS4, PM1, PM3, PM3_P, PP1_S, PP3, PP4) |
| SOX10 NM_006941.3 | HL971 | AD | A | chr22: 38379660 | c.125_132del8 | Indel | Leu42fs21Ter | 0 | 813829 | P (PVS1, PM2, PM4, PP3, PP4) | |
| STRC NM_153700.2 | HL927 | AR | Mixed | chr15:43,892,353 -43,910,998 (min) | del entire gene | CNV | - | 0.003 | 1164296 | P (PVS1, PM1, PM3, PM4, PP1, PP3, PP4) | |
| TECTA NM_005422.2 | DF303 | AR | A | chr11:120979969 | c.248C>T | Missense | Thr83Met | 0.003 | 813831 | LP (PM2, PM3_P, PP1_M, PP3, PP4) | |
| TECTA NM_005422.2 | HL277 | AD | S | chr11:121000866 | c.2887G>A | Missense | Ala963Thr | 0 | 0 | 236059 | LP (PM2, PP1_M, PP3, PP4) |
| TECTA NM_005422.2 | DF183 | AD | A | chr11:121058558 | c.6017A>G | Missense | Asp2006Gly | 0 | 0 | 236033 | LP (PM2, PM5, PP1, PP3, PP4) |
| TJP2 NM_001170414.2 | DF180 | AD | S | chr9:71704982 -71840362 dup | dup exons 1-6 | CNV | - | 0 | 0 | 236035 | P (PS4_P, PM1, PM2, PM4, PP1_S, PP3, PP4) |
| TMC1 NM_138691.2 | DF193 | AR | Mixed | chr9:75263573 | c.15insA | Indel | Val6fs12Ter | 0 | 0.003 | 236041 | P (PVS1, PM2, PM4, PP1, PP3, PP4) |
| TMC1 NM_138691.2 | HL1159 | AR | A | chr9:75369733 | c.674C>T | Missense | Pro225Leu | 0 | 0 | 424807 | P (PM2, PM3_S, PP1_M, PP3, PP4) |
Recessive, R; Dominant, D
A, Ashkenazi; M, Mizrahi; S, Sephardi
ACMG classification and criteria legend: P, pathogenic; LP, likely pathogenic; PVS, very strong pathogenicity evidence; PS, strong pathogenicity evidence; PM, moderate pathogenicity evidence; PP, supporting pathogenicity evidence; _S, strong; _M, moderate; _P, supporting
Number of ethnicity-matched hearing controls ranges from 163-500 individuals (326-1000 chromosomes)
Number of unrelated deaf is 105 individuals (210 chromosomes)
Oza AM, DiStefano MT, Hemphill SE et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat. 2018;39(11):1593-1613.
Richards S, Aziz N, Bale S et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.