rs121912673
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM1PM5PP2PP3_StrongPP5BS2
The NM_005159.5(ACTC1):c.941G>A(p.Arg314His) variant causes a missense change. The variant allele was found at a frequency of 0.00000993 in 1,611,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314C) has been classified as Uncertain significance.
Frequency
Consequence
NM_005159.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTC1 | NM_005159.5 | c.941G>A | p.Arg314His | missense_variant | 6/7 | ENST00000290378.6 | |
GJD2-DT | NR_120329.1 | n.299+13732C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTC1 | ENST00000290378.6 | c.941G>A | p.Arg314His | missense_variant | 6/7 | 1 | NM_005159.5 | P1 | |
GJD2-DT | ENST00000671663.1 | n.95-19333C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250904Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135572
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1459276Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 6AN XY: 725360
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74306
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1R Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | KTest Genetics, KTest | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1998 | - - |
Likely pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Aug 24, 2018 | ACMG codes: PS3, PP3, PP5 - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 25, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2023 | 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) - |
Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2023 | 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. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 27, 2023 | This missense variant is located in the myosin head/motor domain of the ACTC1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that this variant may affect protein stability, calcium sensitivity and interaction with MYBPC3 (PMID: 19799913, 22590617, 24736382). However, clinical relevance of these observations is not known. This variant has been reported to segregate with dilated cardiomyopathy in three affected individuals from one family (PMID: 9563954). This variant was also identified in a 15-year-old unaffected relative in this family. Other DCM-associated genes were not tested in this study. This variant has been identified in 4/276578 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While there is a suspicion for a pathogenic role, available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at