rs142839840

Positions:

chr15-34792275-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The ENST00000290378.6(ACTC1):c.623G>A(p.Arg208His) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ACTC1
ENST00000290378.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:1

Conservation

PhyloP100: 6.16

Variant links:

Genes affected

ACTC1 (HGNC:143): (actin alpha cardiac muscle 1) Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC). [provided by RefSeq, Jul 2008]

ACTC1 links:

GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

GJD2-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTC1. . Gene score misZ 4.5244 (greater than the threshold 3.09). Trascript score misZ 6.3156 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, atrial septal defect 5, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1R, hypertrophic cardiomyopathy 11.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTC1	NM_005159.5 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	5/7	ENST00000290378.6	NP_005150.1
GJD2-DT	NR_120329.1 linkuse as main transcript	n.299+14844C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	5/7	1	NM_005159.5	ENSP00000290378	P1
GJD2-DT	ENST00000671663.1 linkuse as main transcript	n.95-18221C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251470

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 520473; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28416588, 32880476, 30471092, 28798025) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Mar 31, 2017

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 26, 2023

This missense variant replaces arginine with histidine at codon 208 of the ACTC1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four individuals affected with dilated cardiomyopathy (PMID: 28416588, 30847666, 32880476 and 34935411) and two individuals affected with left ventricular non-compaction (PMID: 28798025, 30471092). This variant has been identified in 10/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt ACTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 520473). This missense change has been observed in individual(s) with dilated cardiomyopathy or left ventricular noncompaction cardiomyopathy (PMID: 28416588, 28798025, 30471092, 32880476, 34088380). This variant is present in population databases (rs142839840, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 208 of the ACTC1 protein (p.Arg208His). -

ACTC1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2022

The ACTC1 c.623G>A variant is predicted to result in the amino acid substitution p.Arg208His. This variant was reported in individuals with dilated cardiomyopathy or left ventricular noncompaction; however, the pathogenicity was not established (Table S1, Dal Ferro et al. 2017. PubMed ID: 28416588; Table S3, Miszalski-Jamka et al. 2017. PubMed ID: 28798025; Richard et al. 2018. PubMed ID: 30471092; Table S4, Verdonschot et al. 2020. PubMed ID: 32880476; Table S2, Cambon-Viala et al. 2021. PubMed ID: 34088380). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-35084476-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/520473/). A different nucleotide substitution affecting the same amino acid (p.Arg208Cys) has been reported in an individual with left ventricular noncompaction (Table S2, Mazzarotto et al. 2021. PubMed ID: 33500567). At this time, the clinical significance of the c.623G>A (p.Arg208His) variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 08, 2024

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The p.R208H variant (also known as c.623G>A), located in coding exon 4 of the ACTC1 gene, results from a G to A substitution at nucleotide position 623. The arginine at codon 208 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in cardiomyopathy cohorts, including dilated cardiomyopathy (DCM), left ventricular non-compaction (LVNC), and pediatric cardiomyopathy cohorts; however, clinical details were limited, and additional cardiac variants were detected in some cases (Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[ePub ahead of print]; Richard P et al. Clin Genet, 2019 03;95:356-367; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487; Cambon-Viala M et al. J Card Fail, 2021 06;27:677-681; Khan RS et al. J Am Heart Assoc, 2022 01;11:e022854). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Left ventricular noncompaction 1;C2677506:Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 12-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

CardioboostCm

Uncertain

0.68

BayesDel_addAF

Benign

0.0082

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.61

Sift4G

Benign

0.064

Polyphen

0.0

Vest4

0.39

MVP

0.89

MPC

3.3

ClinPred

0.60

GERP RS

4.9

Varity_R

0.90

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over