ClinVar Miner

Submissions for variant NM_001614.5(ACTG1):c.1036C>G (p.Leu346Val)

dbSNP: rs782217473
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000216408 SCV000271490 uncertain significance not specified 2015-05-22 criteria provided, single submitter clinical testing The p.Leu346Val variant in ACTG1 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational p rediction tools and conservation analysis suggest that the variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Leu346Val variant is unce rtain.
Athena Diagnostics RCV000991476 SCV001142899 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing
GeneDx RCV000991476 SCV004030738 likely pathogenic not provided 2023-08-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV003765386 SCV004595250 likely pathogenic Autosomal dominant nonsyndromic hearing loss 20; Baraitser-winter syndrome 2 2023-06-19 criteria provided, single submitter clinical testing 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 not expected to disrupt ACTG1 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 228431). This missense change has been observed in individual(s) with clinical features of Baraitser-Winter syndrome (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 346 of the ACTG1 protein (p.Leu346Val).

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