rs727502886

Positions:

• chr1-236719007-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The ENST00000366578.6(ACTN2):​c.355G>A​(p.Ala119Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTN2 ENST00000366578.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

Genes affected

ACTN2 (HGNC:164): (actinin alpha 2) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 1-236719007-G-A is Pathogenic according to our data. Variant chr1-236719007-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN2	NM_001103.4	c.355G>A	p.Ala119Thr	missense_variant	3/21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2	c.355G>A	p.Ala119Thr	missense_variant	3/21		NP_001265272.1
ACTN2	NR_184402.1	n.530G>A		non_coding_transcript_exon_variant	3/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6	c.355G>A	p.Ala119Thr	missense_variant	3/21	1	NM_001103.4	ENSP00000355537	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461736 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

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: 0.0000187

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 06, 2014

The p.Ala119Thr variant in ACTN2 has previously been reported in a large Austral ian family with HCM, segregated with disease in 6 affected relatives including o ne obligate carrier (Chiu 2006). It was absent from large population studies. Th is variant meets our criteria to be classified as pathogenic for HCM based upon segregation studies and absence from controls. -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 119 of the ACTN2 protein (p.Ala119Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, left ventricular noncompaction, and/or ventricular fibrillation (PMID: 20022194, 25224718, 32931854, 35656879). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162727). 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 ACTN2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACTN2 function (PMID: 27287556). For these reasons, this variant has been classified as Pathogenic. -

ACTN2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Mar 19, 2020

This variant has been previously reported as a heterozygous change and segregating with disease in families with cardiac phenotype heterogeneity. Phenotypes included dilated cardiomyopathy, left ventricular noncompaction, ventricular fibrillation, and sudden death (PMID: 20022194, 25224718). Functional characterization of the variant demonstrated reduced F-actin binding affinity and altered Z-disc localization and dynamics (PMID: 27287556). It is absent from the gnomAD population database and thus is presumed to be rare. The c.355G>A (p.Ala119Thr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. ClinVar contains an entry for this variant (Variation ID: 162727). Based on the available evidence, the c.355G>A (p.Ala119Thr) variant is classified as Pathogenic. -

Dilated cardiomyopathy 1AA Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 16, 2014

- -

Cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 16, 2014

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2024

The p.A119T variant (also known as c.355G>A), located in coding exon 3 of the ACTN2 gene, results from a G to A substitution at nucleotide position 355. The alanine at codon 119 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC) and sudden death and has been shown to segregate with disease (Chiu C et al. J Am Coll Cardiol, 2010 Mar;55:1127-35; Bagnall RD et al. BMC Med Genet, 2014 Sep;15:99; Kraoua L et al. Mol Genet Genomic Med, 2022 Jul;10:e1954; Isbister JC et al. Int J Cardiol, 2021 Feb;324:96-101). This alteration may also have an impact on protein function (Haywood NJ et al. Biochem J, 2016 Aug;473:2485-93). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.85
MutPred		0.90		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.78

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: rs727502886; hg19: chr1-236882307;