Submissions for variant NM_138691.3(TMC1):c.1939T>C (p.Ser647Pro)

gnomAD frequency: 0.00002  dbSNP: rs138527651

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221167	SCV000271466	pathogenic	Rare genetic deafness	2015-08-10	criteria provided, single submitter	clinical testing	The p.Ser647Pro variant in TMC1 has been reported in >10 Moroccan Jewish individ uals with hearing loss and segregated with disease in 8 affected relatives from 5 families (Brownstein 2011). All of these individuals were homozygous or compou nd heterozygous and all unaffected family members were either heterozygous only or wild-type at this position. The variant was also identified in 16/282 (5.6%) control individuals of Moroccan Jewish ancestry, all of whom were heterozygous f or the variant, which suggests that this variant represents a founder mutation f or hearing loss in this population (Brownstein 2011). In summary, this variant m eets our criteria to be classified as pathogenic for hearing loss in an autosoma l recessive manner based on segregation studies and its co-occurrence with a sec ond pathogenic TMC1 variant in many affected, unrelated individuals.
Revvity Omics, Revvity	RCV001782704	SCV002018978	pathogenic	not provided	2019-07-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001782704	SCV003805702	likely pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	S647P has been described as a founder mutation, contributing to nearly a third of genetic hearing loss among the Moroccan Jewish population (Brownstein et al., 2011; Ehrenberg et al., 2019); 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: 22269275, 21917145, 24933710, 31814694, 31589614, 34795337, 24156272, Aboagye2023[paper], 27344577)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001782704	SCV004294329	pathogenic	not provided	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 647 of the TMC1 protein (p.Ser647Pro). This variant is present in population databases (rs138527651, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 21917145, 31814694). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228408). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMC1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000225028	SCV000282004	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2016-02-19	no assertion criteria provided	research	Congenital, profound HL