Submissions for variant NM_138691.3(TMC1):c.1398CAA[1] (p.Asn467del)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003557451	SCV004294324	likely pathogenic	not provided	2024-10-09	criteria provided, single submitter	clinical testing	This variant, c.1401_1403del, results in the deletion of 1 amino acid(s) of the TMC1 protein (p.Asn467del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs780156287, gnomAD 0.02%). This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 25458163, 29533536, 31854501). 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. This variant is also known as c.1399_1401delAAC (p.Asn466del) and c.1396_1398delAAC (p.Asn466del). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV003557451	SCV005325187	likely pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	In-frame deletion of 11 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29533536, 25458163, 31854501)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005063024	SCV005726030	likely pathogenic	Nonsyndromic genetic hearing loss	2024-11-22	criteria provided, single submitter	clinical testing	Variant summary: TMC1 c.1401_1403delCAA (p.Asn467del; also known as c.1396_1398AAC; p.Asn466del in the literature) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251230 control chromosomes (gnomAD). c.1401_1403delCAA has been reported in the literature in individuals affected with nonsyndromic hearing loss and deafness (examples: Jiang_2018, Lin_2014, Ramzan_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29533536, 25458163, 31854501). ClinVar contains an entry for this variant (Variation ID: 2735281). Based on the evidence outlined above, the variant was classified as likely pathogenic.