rs1553255521

Positions:

• chr1-229433007-C-A
• chr1-229433007-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5_Strong PS2 PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001100.4(ACTA1):c.109G>T variant in ACTA1 is a missense variant predicted to cause substitution of valine by leucine at amino acid 37 (legacy nomenclature: p.Val35Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.881, 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). Three other variants occur at the same residue (c.110T>C (p.V37A); c.110T>G (p.V37G)) with c.109G>C (p.V37L) occurring at the same nucleotide (PM5_Strong). This variant has occurred de novo in one individual with nemaline myopathy, hypotonia, respiratory distress, and cardiac arrest (PS2; PMID:28973083, Baylor Genetics, SCV000807332.1). 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: PS2, PM5_Strong, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA345151305/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.88

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.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.109G>T	p.Val37Leu	missense_variant	2/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.109G>T	p.Val37Leu	missense_variant	2/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.109G>T	p.Val37Leu	missense_variant	2/7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.-6-127G>T		intron_variant				ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Actin accumulation myopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously described as disease-causing in the literature, as has another mutation causing the same amino acid substitution. It has been identified once in our laboratory as a de novo mutation in a 1-month-old female with nemaline myopathy, hypotonia, respiratory distress, and cardiac arrest -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2017	This variant has been reported in an individual affected with nemaline myopathy (PMID: 19562689, 23394784). In summary, this variant is a rare missense change that has been reported in multiple affected individuals. For these reasons, it has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different nucleotide change (c.109G>C) that produces the same amino acid change as this variant (p.Val37Leu) has been reported in multiple individuals affected with nemaline myopathy (PMID: 19562689, 12921789, 15236405). In 2 of these cases this variant was reported to arise de novo (PMID: 19562689, 12921789, 15236405). The c.109G>C sequence change has also been reported as p.Val35Leu. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 37 of the ACTA1 protein (p.Val37Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -
Pathogenic, criteria provided, single submitter	provider interpretation	Pediatric Department, Peking University First Hospital	Apr 11, 2020	- -

Alpha-actinopathy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 27, 2024

The NM_001100.4(ACTA1):c.109G>T variant in ACTA1 is a missense variant predicted to cause substitution of valine by leucine at amino acid 37 (legacy nomenclature: p.Val35Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.881, 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). Three other variants occur at the same residue (c.110T>C (p.V37A); c.110T>G (p.V37G)) with c.109G>C (p.V37L) occurring at the same nucleotide (PM5_Strong). This variant has occurred de novo in one individual with nemaline myopathy, hypotonia, respiratory distress, and cardiac arrest (PS2; PMID:28973083, Baylor Genetics, SCV000807332.1). 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: PS2, PM5_Strong, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2024

Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19562689, 22759684, 23394784, 25326635, 35081925, 28973083, 12921789, 15236405) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.62	P;.
Vest4		0.85
MutPred		0.92		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.97
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.90
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553255521; hg19: chr1-229568754;