rs1555418829

Positions:

• chr15-34792492-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005159.5(ACTC1):​c.532A>T​(p.Met178Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 6.17

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTC1	NM_005159.5	c.532A>T	p.Met178Leu	missense_variant	4/7	ENST00000290378.6	NP_005150.1
GJD2-DT	NR_120329.1	n.299+15061T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6	c.532A>T	p.Met178Leu	missense_variant	4/7	1	NM_005159.5	ENSP00000290378	P1
GJD2-DT	ENST00000671663.1	n.95-18004T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 22, 2022	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 178 of the ACTC1 protein (p.Met178Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with isolated secundum atrial septal defect (PMID: 24461919). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 517203). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 06, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Met178Leu variant in ACTC1 has been identified via exome sequencing in 1 Caucasian family with Atrial Septal Defect. The variant was present in 4 affected individuals an d 1 obligate carrier and was not absent in the one unaffected individual tested (Greenway 2014). This variant was absent from large population studies. Computat ional prediction tools and conservation analysis are suggest that the p.Met178Le u variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The ACTC1 gene has previously been associated with ASD (Matson 2008) but the overall data linking this gene to ASD is still li mited. Therefore, while there is some suspicion that the Met178Leu variant caus es ASD its clinical significance is uncertain. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2023

This missense variant replaces methionine with leucine at codon 178 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 five related individuals affected with atrial septal defect (PMID: 24461919). It has been shown that this variant segregates with disease in this family. This variant has not been identified 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2021

The p.M178L variant (also known as c.532A>T), located in coding exon 3 of the ACTC1 gene, results from an A to T substitution at nucleotide position 532. The methionine at codon 178 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in several affected members of a family with atrial septal defect (Greenway SC et al. Can J Cardiol, 2014 Feb;30:181-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.18
Eigen_PC	Benign	0.074
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	-0.87	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.31	N
REVEL	Uncertain	0.51
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.82
MutPred		0.30		Gain of sheet (P = 0.0827);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.90

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

Other links and lift over

dbSNP: rs1555418829; hg19: chr15-35084693;