ClinVar Miner

Submissions for variant NM_001614.5(ACTG1):c.914T>C (p.Met305Thr)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion RCV002283966 SCV002573238 uncertain significance Autosomal dominant nonsyndromic hearing loss 20 2022-09-01 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ACTG1-related disorder (PMID: 23506231). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV005227568 SCV005863405 pathogenic Autosomal dominant nonsyndromic hearing loss 20; Baraitser-winter syndrome 2 2024-12-05 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 305 of the ACTG1 protein (p.Met305Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with deafness (PMID: 23506231). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1705652). 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 ACTG1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

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