NM_005159.5(ACTC1):c.941G>A (p.Arg314His) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003996110.2

Allele description [Variation Report for NM_005159.5(ACTC1):c.941G>A (p.Arg314His)]

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

Genes:

GJD2-DT:GJD2 divergent transcript [Gene - HGNC]
ACTC1:actin alpha cardiac muscle 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q14

Genomic location:

Preferred name:

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

Other names:

R312H

HGVS:

NC_000015.10:g.34791163C>T
NG_007553.1:g.9564G>A
NM_005159.5:c.941G>AMANE SELECT
NP_005150.1:p.Arg314His
LRG_388t1:c.941G>A
LRG_388:g.9564G>A
LRG_388p1:p.Arg314His
NC_000015.9:g.35083364C>T
NM_005159.4:c.941G>A
P68032:p.Arg314His

Protein change:

R314H; ARG312HIS

Links:

UniProtKB: P68032#VAR_012860; OMIM: 102540.0001; dbSNP: rs121912673

NCBI 1000 Genomes Browser:

rs121912673

Molecular consequence:

NM_005159.5:c.941G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004844810	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9563954, 19799913, 22590617, 24736382, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004844810

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 27, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Actin mutations in dilated cardiomyopathy, a heritable form of heart failure.

Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT.

Science. 1998 May 1;280(5364):750-2.

PubMed [citation]

PMID:: 9563954

Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro.

Debold EP, Saber W, Cheema Y, Bookwalter CS, Trybus KM, Warshaw DM, Vanburen P.

J Mol Cell Cardiol. 2010 Feb;48(2):286-92. doi: 10.1016/j.yjmcc.2009.09.014. Epub 2009 Sep 30.

PubMed [citation]

PMID:: 19799913
PMCID:: PMC2813351

See all PubMed Citations (5)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004844810.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 8, 2024

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