Submissions for variant NM_138691.3(TMC1):c.1714G>A (p.Asp572Asn)

dbSNP: rs121908072

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217542	SCV000271465	pathogenic	Rare genetic deafness	2015-06-05	criteria provided, single submitter	clinical testing	The p.Asp572Asn in TMC1 has been previously reported in 3 probands with nonsyndr omic bilateral sensorineural hearing loss, and segregated with disease in a domi nant pattern in >10 affected family members (Kurima 2002, Hilgert 2009, Makishim a 2004, Wei 2014). The hearing loss was reported to be progressive with a postli ngual onset. The variant was identified in one unaffected individual from one fa mily, indicating that the penetrance may not be complete; however the age of thi s individual was also not reported (Hilgert 2009). This variant was absent from large population databases. A variant affecting the same amino acid (p.Asp572His ) has also been reported in an individual with hearing loss and segregated in 7 affected family members including 2 obligate carriers (Kitajiri 2007), further s upporting that missense variants at this position are not tolerated. Unlike loss of function variants in TMC1, which cause recessive hearing loss, these studies indicate that the p.Asp572Asn and p.Asp572His missense variants cause dominant hearing loss. In summary, the p.Asp572Asn variant meets our criteria to be class ified as pathogenic for autosomal dominant sensorineural hearing loss (http://ww w.partners.org/personalizedmedicine/LMM) based upon segregation studies in affec ted families and its absence in the general population.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000004318	SCV000891297	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 36	2016-09-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810830	SCV001473661	pathogenic	not provided	2020-05-28	criteria provided, single submitter	clinical testing	The TMC1 c.1714G>A; p.Asp572Asn variant (rs121908072) is reported in the literature segregating with disease in several families affected with autosomal dominant hearing loss (Hilgert 2009, Kurima 2002, Wang 2018, Wei 2014). This variant is reported in ClinVar (Variation ID: 4102), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1714G>C; p.Asp572His) has been reported in a large family affected with autosomal dominant hearing loss (Kitajiri 2007). Based on available information, this variant is considered to be pathogenic. References: Hilgert N et al. Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. J Hum Genet. 2009;54(3):188-190. Kitajiri S et al. A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. Clin Genet. 2007;71(2):148-152. Kurima et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002 Mar;30(3):277-84. Wang et al. Identification of four TMC1 variations in different Chinese families with hereditary hearing loss. Mol Genet Genomic Med. 2018 Apr 14. Wei Q et al. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J Transl Med. 2014;12:311. Published 2014 Nov 12.
GeneDx	RCV001810830	SCV002499803	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: severe disruption of LHFPL5 binding (Yu et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17250663, 15354000, 25388789, 26226225, 26079994, 29654653, 31854501, 31541171, 19180119, 11850618, 33168709, 27535533)
OMIM	RCV000004318	SCV000024489	pathogenic	Autosomal dominant nonsyndromic hearing loss 36	2009-03-01	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV000004318	SCV001760240	pathogenic	Autosomal dominant nonsyndromic hearing loss 36		no assertion criteria provided	clinical testing