Submissions for variant NM_138691.3(TMC1):c.46G>A (p.Glu16Lys)

gnomAD frequency: 0.00036  dbSNP: rs140437301

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001166567	SCV001328957	uncertain significance	Autosomal recessive nonsyndromic hearing loss 7	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001166568	SCV001328958	uncertain significance	Autosomal dominant nonsyndromic hearing loss 36	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195528	SCV001365906	uncertain significance	not specified	2019-03-20	criteria provided, single submitter	clinical testing	The p.Glu16Lys variant in TMC1 has not been previously reported in individuals with hearing loss, but has been identified in 0.04% (54/127958) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools predict that this variant does not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4.
GeneDx	RCV001358325	SCV002056078	uncertain significance	not provided	2024-04-18	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358325	SCV002140978	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 16 of the TMC1 protein (p.Glu16Lys). This variant is present in population databases (rs140437301, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TMC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 913097). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TMC1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358325	SCV001554026	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TMC1 p.Glu16Lys variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs140437301) and in control databases in 75 of 280480 chromosomes at a frequency of 0.0002674 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 54 of 127958 chromosomes (freq: 0.000422), Latino in 12 of 35186 chromosomes (freq: 0.000341), African in 4 of 24744 chromosomes (freq: 0.000162), European (Finnish) in 4 of 25034 chromosomes (freq: 0.00016) and Other in 1 of 7158 chromosomes (freq: 0.00014), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Glu16 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.