ClinVar Miner

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

dbSNP: rs374793617
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
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. 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 2020-12-28 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 (Scott et al., 2001); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31589614, 32747562, 30622556, 28695016, 11137999, 24416283, 21786053)
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).
Invitae 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.