Submissions for variant NM_005159.5(ACTC1):c.941G>A (p.Arg314His)

gnomAD frequency: 0.00003  dbSNP: rs121912673

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489472	SCV000577700	likely pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	Identified in patients with DCM and early onset atrial fibrillation in published literature (Olson et al., 1998; Nguyen et al., 2021; Yoneda et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant results in significant reductions in maximal calcium regulated thin filament velocity (Debold et al., 2010); Published functional studies also demonstrate this variant, reported as R312H, results in decreased contractility and filament stability which authors predicted cause filament disarrays in intact cardiomyocytes (Hassoun et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R312H); This variant is associated with the following publications: (PMID: 22590617, 24736382, 31921954, 26061005, 9563954, 19799913, 34930662, 34495297, 34011823, 35457283)
Invitae	RCV000648300	SCV000770114	likely pathogenic	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2023-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 314 of the ACTC1 protein (p.Arg314His). This variant is present in population databases (rs121912673, gnomAD 0.003%). 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. This variant disrupts the p.Arg314 amino acid residue in ACTC1. Other variant(s) that disrupt this residue have been observed in individuals with ACTC1-related conditions (PMID: 9563954, 23283745), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ACTC1 function (PMID: 19799913, 22590617, 24736382). 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 expected to disrupt ACTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 18323). This variant is also known as R312H. This missense change has been observed in individual(s) with clinical features of ACTC1-related conditions (PMID: 9563954, 34011823, 34495297, 34930662). It has also been observed to segregate with disease in related individuals.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000019988	SCV000891768	likely pathogenic	Dilated cardiomyopathy 1R	2018-08-24	criteria provided, single submitter	research	ACMG codes: PS3, PP3, PP5
AiLife Diagnostics, AiLife Diagnostics	RCV000489472	SCV002502926	likely pathogenic	not provided	2022-03-25	criteria provided, single submitter	clinical testing
OMIM	RCV000019988	SCV000040286	pathogenic	Dilated cardiomyopathy 1R	1998-05-01	no assertion criteria provided	literature only
KTest Genetics, KTest	RCV000019988	SCV001499950	likely pathogenic	Dilated cardiomyopathy 1R		no assertion criteria provided	clinical testing