NM_005159.5(ACTC1):c.740G>A (p.Gly247Asp) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 2, 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:: RCV001216367.8

Allele description [Variation Report for NM_005159.5(ACTC1):c.740G>A (p.Gly247Asp)]

NM_005159.5(ACTC1):c.740G>A (p.Gly247Asp)

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.740G>A (p.Gly247Asp)

HGVS:

NC_000015.10:g.34792158C>T
NG_007553.1:g.8569G>A
NM_005159.5:c.740G>AMANE SELECT
NP_005150.1:p.Gly247Asp
LRG_388t1:c.740G>A
LRG_388:g.8569G>A
NC_000015.9:g.35084359C>T
NM_005159.4:c.740G>A

Protein change:

G247D

Links:

dbSNP: rs1566967399

NCBI 1000 Genomes Browser:

rs1566967399

Molecular consequence:

NM_005159.5:c.740G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypertrophic cardiomyopathy 11
Synonyms:: Familial hypertrophic cardiomyopathy 11; ACTC1-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0012799; MedGen: C2677506; OMIM: 612098

Name:: Dilated cardiomyopathy 1R (CMD1R)
Identifiers:: MONDO: MONDO:0013261; MedGen: C3150681; Orphanet: 154; Orphanet: 54260; OMIM: 613424

Name:: Atrial septal defect 5 (ASD5)
Identifiers:: MONDO: MONDO:0013011; MedGen: C2748552; Orphanet: 1478; OMIM: 612794

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001388163	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31434612, 31430208, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001388163

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 2, 2023)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A cardiac α-actin (ACTC1) p. Gly247Asp mutation inhibits SRF-signaling in vitro in neonatal rat cardiomyocytes.

Rangrez AY, Kilian L, Stiebeling K, Dittmann S, Schulze-Bahr E, Frey N, Frank D.

Biochem Biophys Res Commun. 2019 Oct 20;518(3):500-505. doi: 10.1016/j.bbrc.2019.08.081. Epub 2019 Aug 18.

PubMed [citation]

PMID:: 31434612

Cardiac α-Actin (ACTC1) Gene Mutation Causes Atrial-Septal Defects Associated With Late-Onset Dilated Cardiomyopathy.

Frank D, Yusuf Rangrez A, Friedrich C, Dittmann S, Stallmeyer B, Yadav P, Bernt A, Schulze-Bahr E, Borlepawar A, Zimmermann WH, Peischard S, Seebohm G, Linke WA, Baba HA, Krüger M, Unger A, Usinger P, Frey N, Schulze-Bahr E.

Circ Genom Precis Med. 2019 Aug;12(8):e002491. doi: 10.1161/CIRCGEN.119.002491. Epub 2019 Aug 20.

PubMed [citation]

PMID:: 31430208

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001388163.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACTC1 function (PMID: 31430208, 31434612). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 626827). This missense change has been observed in individual(s) with atrial septal defect and/or dilated cardiomyopathy (PMID: 31430208). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 247 of the ACTC1 protein (p.Gly247Asp).

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

Last Updated: Sep 29, 2024

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