ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.941G>A (p.Arg314His) (rs121912673)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489472 SCV000577700 likely pathogenic not provided 2018-04-16 criteria provided, single submitter clinical testing The R314H variant (denoted as R312H, due to a difference in nomenclature) in the ACTC1 gene has been reported to co-segregate with DCM in three affected individuals in one family (Olson et al., 1998). R314H was absent in 800 control chromosomes in this study. However, R314H was also identified in a 15-year-old unaffected relative. Furthermore, genetic testing of other DCM-associated genes was not performed, therefore, the possibility that other disease-causing variants may be present in this family cannot be excluded (Olson et al., 1998). Nevertheless, in vitro studies demonstrated that the R314H variant caused significant reductions in thin filament velocity and increased calcium sensitivity (Debold et al., 2010). Additional studies demonstrated that the R314H ACTC1 mutant protein possessed reduced protein stability accompanied with a higher polymerization critical concentration, and higher rates of inorganic phosphate release (Mundia et al., 2012). This variant is located in subdomain 3, a region of actin that is proposed to make important electrostatic contacts with tropomyosin (Debold et al., 2010).Although R314H results in a conservative amino acid substitution, this substitution occurs at a position that is conserved across species. A different variant in the same residue (R314C) as well as other variants in nearby residues (M307L, D313H, A323V) have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Lastly, the R314H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Invitae RCV000648300 SCV000770114 likely pathogenic Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 314 of the ACTC1 protein (p.Arg314His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy (DCM) in a single family (PMID: 9563954). This variant is also known as R312H in the literature. ClinVar contains an entry for this variant (Variation ID: 18323). Experimental studies have shown that this missense change reduces myosin motility and protein stability, but increases calcium sensitivity, nucleotide and inorganic phosphate (Pi) release in vitro (PMID: 19799913, 22590617, 24736382). The observation of one or more missense substitutions at this codon (p.Arg314His and p.Arg314Cys) in affected individuals suggests that this may be a clinically significant residue (PMID: 9563954, 23283745). 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.
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
Color RCV001177580 SCV001341817 uncertain significance Cardiomyopathy 2018-11-09 criteria provided, single submitter clinical testing
OMIM RCV000019988 SCV000040286 pathogenic Dilated cardiomyopathy 1R 1998-05-01 no assertion criteria provided literature only

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