NM_001100.4:c.493G>A

Variant names:

• chr1-229432393-C-T
• rs121909522
• NM_001100.4:c.493G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2 PP3 PM2_Supporting PS3 PP4_Moderate PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.493G>A variant in ACTA1 is a missense variant predicted to cause substitution of valine by methionine at amino acid 165 (legacy nomenclature: p.Val163Met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In vitro studies in C2C12 myoblasts showed that V165M formed intranuclear actin aggregates with low levels of cytoplasmic aggregates, indicating that this variant impacts protein function. These oblong intranuclear aggregates closely resembled intranuclear bodies observed in muscle samples from patients with intranuclear myopathy. Additionally, Drosophila heterozygous for V165M show that V165M can severely affect Z-disc assembly and the stability of the sarcomere. Heterozygous V165M Drosophila presented with zebra bodies, Z-rings, and intranuclear rods (PS3; PMID:15198992, 17705262, 23294764). This variant has been reported in 1 proband with intranuclear rod myopathy confirmed by biopsy (PP4_Moderate; PMID:12921789). The variant has been reported to segregate with nemaline myopathy in 2 affected family members from 1 family (PP1_Moderate; PMID:12921789). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS3, PP4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PP2 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA258144/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.76

Genes affected

ACTA1 (HGNC:129): (actin alpha 1, skeletal muscle) The product encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Mutations in this gene cause a variety of myopathies, including nemaline myopathy, congenital myopathy with excess of thin myofilaments, congenital myopathy with cores, and congenital myopathy with fiber-type disproportion, diseases that lead to muscle fiber defects with manifestations such as hypotonia. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.493G>A	p.Val165Met	missense_variant	Exon 4 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.493G>A	p.Val165Met	missense_variant	Exon 4 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.493G>A	p.Val165Met	missense_variant	Exon 4 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.358G>A	p.Val120Met	missense_variant	Exon 3 of 6			ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Actin accumulation myopathy Pathogenic:2

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 165 of the ACTA1 protein (p.Val165Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Nemaline myopathy (PMID: 15198992, 16427282). It has also been observed to segregate with disease in related individuals. This variant is also known as V163M. ClinVar contains an entry for this variant (Variation ID: 18292). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 15198992, 17705262). This variant disrupts the p.Val165 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been observed in individuals with ACTA1-related conditions (PMID: 10508519), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Dec 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACTA1: PM2, PM5, PS4:Moderate, PP1, PP2, PP3, PS3:Supporting -

Apr 05, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alpha-actinopathy Pathogenic:1

Aug 27, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.493G>A variant in ACTA1 is a missense variant predicted to cause substitution of valine by methionine at amino acid 165 (legacy nomenclature: p.Val163Met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In vitro studies in C2C12 myoblasts showed that V165M formed intranuclear actin aggregates with low levels of cytoplasmic aggregates, indicating that this variant impacts protein function. These oblong intranuclear aggregates closely resembled intranuclear bodies observed in muscle samples from patients with intranuclear myopathy. Additionally, Drosophila heterozygous for V165M show that V165M can severely affect Z-disc assembly and the stability of the sarcomere. Heterozygous V165M Drosophila presented with zebra bodies, Z-rings, and intranuclear rods (PS3; PMID:15198992, 17705262, 23294764). This variant has been reported in 1 proband with intranuclear rod myopathy confirmed by biopsy (PP4_Moderate; PMID:12921789). The variant has been reported to segregate with nemaline myopathy in 2 affected family members from 1 family (PP1_Moderate; PMID: 12921789). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS3, PP4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PP2 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.96
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.92		Gain of loop (P = 0.1069);
MVP		0.99
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.97

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: rs121909522; hg19: chr1-229568140; COSMIC: COSV64203141;