Submissions for variant NM_005159.5(ACTC1):c.383C>T (p.Thr128Ile)

dbSNP: rs727504308

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001723721	SCV001985351	likely pathogenic	not provided	2024-06-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 36158814, 22464770)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857531	SCV002224459	likely pathogenic	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 128 of the ACTC1 protein (p.Thr128Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 22464770; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177748). 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 ACTC1 protein function with a negative predictive value of 80%. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154361	SCV000204024	uncertain significance	not specified	2013-01-23	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723721	SCV001958067	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723721	SCV001969231	pathogenic	not provided		no assertion criteria provided	clinical testing