Submissions for variant NM_001256317.3(TMPRSS3):c.323-6G>A

dbSNP: rs374793617

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039350	SCV000063034	pathogenic	Rare genetic deafness	2013-10-17	criteria provided, single submitter	clinical testing	The 323-6G>A variant in TMPRSS3 has been reported in homozygosity in one individ ual with hearing loss (Scott 2001). It has also been identified by our laborator y in trans with another pathogenic variant in one individual with hearing loss. The variant is located in the 3' splice region and studies have shown that the 323-6G>A variant impacts splicing and leads to a frameshift (Scott 2001). Althou gh this variant has been identified in 0.02% (1/4406) of African American chromo somes from a broad population by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS) and in 1/160 Muslim Indians controls (Scott 2001), this f requency is low enough to be consistent with a recessive carrier frequency. In s ummary, this variant meets our criteria to be classified as pathogenic.
National Institute on Deafness and Communication Disorders, National Institutes of Health	RCV001328013	SCV001519346	pathogenic	Childhood onset hearing loss	2021-07-08	criteria provided, single submitter	research	PS1, PS3_moderate, PM2, PM3_strong, PP3 / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375193	SCV001571847	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Moderate PM2_Supporting, BP4_Supporting
GeneDx	RCV001558268	SCV001780180	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect caused by the insertion of 4 nucleotides between exons 4 and 5 and leading to a frameshift (PMID: 11137999); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 11137999, 30622556, 34868270, 21786053, 24416283, 28695016, 32747562, 31589614, 34837038)
Revvity Omics, Revvity	RCV001781358	SCV002020238	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2019-10-14	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV001781358	SCV002556415	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-07-01	criteria provided, single submitter	clinical testing	The TMPRSS3 c.323-6G>A variant is classified as PATHOGENIC (PVS1, PS4, PM3) The TMPRSS3 c.323-6G>A variant is located in a splice acceptor region. Studies have demonstrated this variant impacts splicing, leading to a frameshift in the open reading frame (PMID:11137999) (PVS1). This variant has been reported in both a homozygous and compound heterozygous state in multiple individuals with deafness, in the literature (PMID:11137999; PMID:30622556; PMID:34868270) (PS4) (PM3). This variant is in dbSNP (rs374793617) but is rare in population databases (gnomAD 4/152118, no homozygotes). This variant has been reported in ClinVar as Pathogenic for Hearing loss by other diagnostic laboratories (Variation ID: 46113) and as damaging in the HGMD disease database for childhood onset deafness (CS010098).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001558268	SCV003444360	pathogenic	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the TMPRSS3 gene. It does not directly change the encoded amino acid sequence of the TMPRSS3 protein. This variant is present in population databases (rs374793617, gnomAD 0.03%). This variant has been observed in individual(s) with deafness (PMID: 11137999). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 46113). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11137999). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV001781358	SCV000025408	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2001-01-01	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291485	SCV001479989	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004754286	SCV005348220	pathogenic	TMPRSS3-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The TMPRSS3 c.323-6G>A variant is predicted to interfere with splicing. This variant has been reported in both the homozygous and compound heterozygous states in several individuals with hearing loss, and the change segregates with the hearing loss phenotype in families (Ganapathy et al. 2014. PubMed ID: 24416283; Gao et al. 2017. PubMed ID: 28695016; Morgan et al. 2018. PubMed ID: 30622556). RNA functional studies show that this intronic change alters splicing, resulting in an early protein termination (Scott et al. 2001. PubMed ID: 11137999, alternate nomenclature IVS4-6G>A, p.Cys107fs). This variant is reported in 0.029% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.