. 2021 May 27;185(8):2417–2433. doi: 10.1002/ajmg.a.62347

TABLE 2.

TSPEAR variant ACMG classification

Variant					Variant interpretation					Sequencing method	References
Patient	Gene	Nucleotide change	Amino acid	Zygosity	CADD score	GnomAD AF	ClinVar clinical significance	ACMG classification	Evidence	Sequencing method	References
1	TSPEAR	c.533C>T	p.Pro178Leu	Hom	17.86	0.00003668	NA	VUS	PM2, PP3, BP5	Hearing loss panel	Newly reported
1	TMPRSS3	c.1204G>A	p.Gly402Arg	Hom	31	0	NA	VUS	PM2, PP3, BP5	Hearing loss panel	Newly reported
2	TSPEAR	c.1163T>C	p.Val388Ala	Hom	33	0	NA	VUS	PM2, PP3, BP5	Hearing loss panel	Newly reported
2	TMPRSS3	c.1211C>T	p.Pro404Leu	Hom	26.1	0.00001193	Pathogenic	Likely pathogenic	PP1, PM2, PM3, PP3, PM1, BP5	Hearing loss panel	Newly reported
3	TSPEAR	c.1726_1728delGTCinsTT^a	p.Val576Leufs*38	Hom	33	0	Likely pathogenic	Pathogenic	PVS1, PM2, PP3	WES	Delmaghani et al. (2012)
4	TSPEAR	c.1566G>A	p.Pro522Pro	Het	33	0.00007454	NA	VUS	PM2, PM3, PP3	Hearing loss panel	Sloan‐Heggen et al. (2016)
4	TSPEAR	c.1676_1677delAT	p.Tyr559Cysfs*134	Het	31	0	Pathogenic/Likely pathogenic	Pathogenic	PVS1, PM2, PP3	Hearing loss panel	Sloan‐Heggen et al. (2016)
5	TSPEAR	c.38delT	p.Leu13Argfs*38	Het	24.6	0.00008334	NA	Pathogenic	PVS1, PM2, PM3, PP3, BP5	Hearing loss panel	Newly reported
	TSPEAR	c.589C>T	p.Arg197*	Het	36	0.000305	Conflicting	Pathogenic	PVS1, PM2, PM3, PP3, BP5
	GJB2	c.35delG	p.Gly12Valfs*2	Het	25.3	0.006188	Pathogenic	Pathogenic	PVS1, PS3, PS4, PM2, PP1‐S, PP3, BP5
	GJB6	del(GJB6‐D13S1854)	NA	Het	NA	NA	Pathogenic	Pathogenic	PVS1, PS3, PS4, PP1‐S, PM2, BP5
6	TSPEAR	c.1915G>A	p.Asp639Asn	Het	28.2	0.002251	Conflicting	VUS	PM2, PM3, PP3, BS2	WES	Newly reported
6	TSPEAR	c.589C>T	p.Arg197*	Het	36	0.000305	Conflicting	Pathogenic	PVS1, PM2, PP3	WES	Newly reported
7	TSPEAR	c.1915G>A	p.Asp639Asn	Het	28.2	0.002251	Conflicting	VUS	PM2, PP3, BS2	WES	Newly reported
7	TSPEAR	c.1754G>T	p.Ser585Ile	Het	25.6	0.00006734	Uncertain significance	VUS	PM2, PP3	WES	Newly reported
8	TSPEAR	c.589C>T	p.Arg197*	Het	36	0.000305	Conflicting	Pathogenic	PVS1, PM2, PM3, PP3	WES	Newly reported
8	TSPEAR	c.83‐13708_1566+248del	NA	Het	NA	NA	NA	Pathogenic	PVS1, PM2, PM3, PP3	WES	Newly reported
9	TSPEAR	c.1574G>A	p.Gly525Asp	Het	24.2	0.00003199	NA	VUS	PM2, PM3, PP3	WES	Newly reported
9	TSPEAR	c.543‐1G>A	NA	Het	23.9	0.000007119	NA	Pathogenic	PVS1, PM2, PP3	WES	Newly reported
10	TSPEAR	c.942C>G	p.Tyr314*	Het	36	0	Likely pathogenic	Pathogenic	PVS1, PM2, PP3	WES	Newly reported
10	TSPEAR	c.1469T>A	p.Leu490Gln	Het	29.7	0.00005569	Uncertain significance	VUS	PM2, PM3, PP3	WES	Newly reported
11	TSPEAR	c.1726_1728delGTCinsTT	p.Val576Leufs*38	Hom	33	0	Likely pathogenic	Pathogenic	PVS1, PM2, PP3	WES	Peled et al. (2016)
12	TSPEAR	c.1726_1728delGTCinsTT	p.Val576Leufs*38	Het	33	0	Likely pathogenic	Pathogenic	PVS1, PM2, PP3	WES	Peled et al. (2016)
12	TSPEAR	c.454_457delCTGG	p.Leu152Trpfs*29	Het	23.3	0.000004063	Pathogenic	Pathogenic	PVS1, PM2, PP3	WES	Peled et al. (2016)
13	TSPEAR	c.1852T>A	p.Tyr618Asn	Het	32	0.0000199	Pathogenic	VUS	PM2, PP3	WES	Peled et al. (2016)
13	TSPEAR	c.1915G>A	p.Asp639Asn	Het	28.2	0.002251	Conflicting	VUS	PM2, PP3, BS2	WES	Peled et al. (2016)
14	TSPEAR	c.240T>G	p.Cys80Trp	Het	23.3	0	NA	VUS	PM2, PM3, PP3	Ectodermal dysplasia panel; Sanger sequencing	Newly reported
14	TSPEAR	c.633+2C>A	NA	Het	22.7	0.000004001	NA	Pathogenic	PVS1, PM2, PP3	Ectodermal dysplasia panel; Sanger sequencing	Newly reported
15	TSPEAR	c.1505delA	p.Lys502Argfs*67	Hom	18.1	0.00001592	NA	Pathogenic	PVS1, PM2, PP3	SNP array; Sanger sequencing	Newly reported
16	TSPEAR	c.1726_1728delinsTT	p.Val576Leufs*38	Het	33	0	Likely pathogenic	Pathogenic	PVS1, PM2, PM3, PP3	WES	Newly reported
	TSPEAR	c.589C>T	p.Arg197*	Het	36	0.000305	Conflicting	Pathogenic	PVS1, PM2, PP3, PM3
	ATP1A3	c.2767G>A	p.Asp923Asn	Het	23.8	0	Pathogenic	Likely pathogenic	PS1, PM1, PM2, PP3
17	TSPEAR	c.1915G>A	p.Asp639Asn	Het	28.2	0.002251	Conflicting	VUS	PM2, PP3, BS2	GenoDENT: dental anomalies panel; Sanger sequencing	Newly reported
17	TSPEAR	c.1331G>A	p.Arg444Gln	Het	28.5	0.00008862	NA	VUS	PM2, PP3	GenoDENT: dental anomalies panel; Sanger sequencing	Newly reported
18	TSPEAR	c.1663C>T	p.Gln555*	Het	39	0	NA	Pathogenic	PVS1, PM2, PM3, PP3	GenoDENT: dental anomalies panel; Sanger sequencing	Newly reported
18	TSPEAR	c.1899dup	p.Thr634Hisfs*60	Het	34	0	NA	Pathogenic	PVS1, PM2, PM3, PP3	GenoDENT: dental anomalies panel; Sanger sequencing	Newly reported
19	TSPEAR	c.1726_1728delGTCinsTT	p.Val576Leufs*38	Hom	33	0	Likely pathogenic	Pathogenic	PVS1, PM2, PP3	WES	Du et al. (2018)
20	TSPEAR	c. 1877T>C	p.Phe626Ser	Hom	28.5	0.0001401	NA	VUS	PM2, PP3	WES	Du et al. (2018)
21	TSPEAR	c.1528C>T	p.Arg510*	Het	37	0.0003256	Uncertain significance	Pathogenic	PVS1, PM2, PP3	WES	Song et al. (2020)
21	TSPEAR	c.1330C>T	p.Arg444Trp	Het	25.8	0.00001595	Uncertain significance	VUS	PM2, PM3, PP3	WES	Song et al. (2020)

Note: All variants in this study were classified according to American College of Medical Genetics (ACMG) 2015 criteria. Classifications are shown here, along with the evidence used to support each classification such as combined annotation dependent depletion (CADD) score and genome aggregation database (GnomAD) allele frequency. While numerous suspected pathogenic TSPEAR variants have been reported in the literature, these studies did not report ACMG scoring criteria. To provide a means of comparing newly reported TSPEAR variants to published TSPEAR variants, these published variants have been scored here using the available evidence. ClinVar accessed January 12, 2021, GnomAD v2.1.1 accessed January 13, 2021.

Abbreviations: AF, allele frequency; CADD, combined annotation dependent depletion; del, deletion; delins, deletion/insertion; dup, duplication; GnomAD, genome aggregation database; NA, not available; VUS, variant of uncertain significance.

^{^a}

Variants for individual 3 were originally reported as homozygous c.1726G>T and c.1728delC variants in cis, which can alternately be reported as c.1726_1728delGTCinsTT (p.Val576Leufs*38).