ClinVar Genomic variation as it relates to human health
NM_005159.5(ACTC1):c.941G>A (p.Arg314His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005159.5(ACTC1):c.941G>A (p.Arg314His)
Variation ID: 18323 Accession: VCV000018323.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q14 15: 34791163 (GRCh38) [ NCBI UCSC ] 15: 35083364 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Apr 20, 2024 Jun 9, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_005159.5:c.941G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005150.1:p.Arg314His missense NC_000015.10:g.34791163C>T NC_000015.9:g.35083364C>T NG_007553.1:g.9564G>A LRG_388:g.9564G>A LRG_388t1:c.941G>A LRG_388p1:p.Arg314His P68032:p.Arg314His - Protein change
- R314H
- Other names
- R312H
- Canonical SPDI
- NC_000015.10:34791162:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
ACTC1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3 | 796 | |
GJD2-DT | - | - | - | GRCh38 | - | 776 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (3) |
criteria provided, single submitter
|
Aug 24, 2018 | RCV000019988.28 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 9, 2023 | RCV000648300.10 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 23, 2023 | RCV000489472.7 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 27, 2023 | RCV003996110.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Mar 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502926.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
Likely pathogenic
(Aug 24, 2018)
|
criteria provided, single submitter
Method: research
|
Dilated cardiomyopathy 1R
Affected status: unknown
Allele origin:
maternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV000891768.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
ACMG codes: PS3, PP3, PP5
Number of individuals with the variant: 1
|
|
Likely pathogenic
(May 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577700.7
First in ClinVar: May 22, 2017 Last updated: Jun 17, 2023 |
Comment:
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); … (more)
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) (less)
|
|
Likely pathogenic
(Jun 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1R
Hypertrophic cardiomyopathy 11 Atrial septal defect 5
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000770114.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
|
|
Uncertain Significance
(Apr 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004844810.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 2
|
|
Pathogenic
(May 01, 1998)
|
no assertion criteria provided
Method: literature only
|
CARDIOMYOPATHY, DILATED, 1R
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000040286.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 36-year-old mother and 2 daughters, aged 5 and 2 years, of German ancestry who had dilated cardiomyopathy (CMD1R; 613424), Olson et al. (1998) … (more)
In a 36-year-old mother and 2 daughters, aged 5 and 2 years, of German ancestry who had dilated cardiomyopathy (CMD1R; 613424), Olson et al. (1998) found a G-to-A substitution in codon 312 in exon 5 of the ACTC gene, resulting in an arg312-to-his (R312H) amino acid substitution. A 15-year-old son likewise had inherited the mutation but had not developed dilated cardiomyopathy. (less)
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Dilated cardiomyopathy 1R
Affected status: yes
Allele origin:
germline
|
KTest Genetics, KTest
Accession: SCV001499950.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Genome sequencing as a first-line diagnostic test for hospitalized infants. | Bowling KM | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34930662 |
Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes. | Yoneda ZT | JAMA cardiology | 2021 | PMID: 34495297 |
Genetic Determinants and Genotype-Phenotype Correlations in Vietnamese Patients With Dilated Cardiomyopathy. | Nguyen TV | Circulation journal : official journal of the Japanese Circulation Society | 2021 | PMID: 34011823 |
Altered interactions between cardiac myosin binding protein-C and α-cardiac actin variants associated with cardiomyopathies. | Chow ML | Archives of biochemistry and biophysics | 2014 | PMID: 24736382 |
Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. | Zou Y | Molecular biology reports | 2013 | PMID: 23283745 |
Subdomain location of mutations in cardiac actin correlate with type of functional change. | Mundia MM | PloS one | 2012 | PMID: 22590617 |
Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro. | Debold EP | Journal of molecular and cellular cardiology | 2010 | PMID: 19799913 |
Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. | Olson TM | Science (New York, N.Y.) | 1998 | PMID: 9563954 |
Text-mined citations for rs121912673 ...
HelpRecord last updated Aug 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.