rs121909531

Variant names:

• chr1-229431633-G-A
• rs121909531
• NM_001100.4:c.1000C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP2 PP3 PP4 PM2_Supporting PS3 PM5

This summary comes from the ClinGen Evidence Repository: The c.1000C>T (NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)) variant in ACTA1 is a missense variant predicted to cause substitution of proline by serine at amino acid 334 (p.Pro334Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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). The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). 2 different missense variants, [p.Pro334Leu, (VCV000532770); p.Pro334Arg, (VCV001031829)], in the same codon have been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). One patient with the p.Pro334Ser variant displayed fiber type disproportion, which is highly specific for alpha-actinopathy (PP4, PMID:15468086 & University of Western Australia internal data). Localization analysis of the mutant in myotubes showed no incorporation into nascent sarcomeres. Analysis in fibroblasts showed diffuse cytoplasmic myc-actin staining (PMID:19206168; PS3). 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: PM2_supporting, PP2, PP3, PM5, PP4, PS3 (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 10/25/24). LINK:https://erepo.genome.network/evrepo/ui/classification/CA341499/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 8.09

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]

ENSG00000290037 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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.
• 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.
• 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.1000C>T	p.Pro334Ser	missense_variant	Exon 7 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.1000C>T	p.Pro334Ser	missense_variant	Exon 7 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000684723.1	c.865C>T	p.Pro289Ser	missense_variant	Exon 6 of 6			ENSP00000508084.1
ACTA1	ENST00000366683.4	c.991-69C>T		intron_variant	Intron 6 of 6	5		ENSP00000355644.4
ENSG00000290037	ENST00000702606.1	n.268G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 ACTA1 protein function. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 19206168). This variant disrupts the p.Pro334 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 334 of the ACTA1 protein (p.Pro334Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital fiber type disproportion (PMID: 15468086). This variant is also known as p.Pro332Ser. ClinVar contains an entry for this variant (Variation ID: 18291). -

Progressive scapulohumeroperoneal distal myopathy Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Alpha-actinopathy Pathogenic:1

Oct 25, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1000C>T (NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)) variant in ACTA1 is a missense variant predicted to cause substitution of proline by serine at amino acid 334 (p.Pro334Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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). The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). 2 different missense variants, [p.Pro334Leu, (VCV000532770); p.Pro334Arg, (VCV001031829)], in the same codon have been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). One patient with the p.Pro334Ser variant displayed fiber type disproportion, which is highly specific for alpha-actinopathy (PP4, PMID: 15468086 & University of Western Australia internal data). Localization analysis of the mutant in myotubes showed no incorporation into nascent sarcomeres. Analysis in fibroblasts showed diffuse cytoplasmic myc-actin staining (PMID: 19206168; PS3). 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: PM2_supporting, PP2, PP3, PM5, PP4, PS3 (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 10/25/24). -

Congenital myopathy 2c, severe infantile, autosomal dominant Pathogenic:1

Nov 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Congenital myopathy with fiber type disproportion Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.92
Sift4G	Benign	0.087	T;T
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.82		Loss of catalytic residue at P334 (P = 0.0085);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.99

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: rs121909531; hg19: chr1-229567380;