1-229432596-G-C

Variant names:

• chr1-229432596-G-C
• rs121909526
• NM_001100.4:c.414C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PP4_Moderate PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_001100.4:c.414C>G in ACTA1 is a missense variant predicted to cause substitution of isoleucine by methionine at amino acid 138 (p.Ile138Met). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.799, which is above the threshold necessary to apply 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 addition, functional studies have demonstrated that this variant severely reduces co-polymerization compared to wild-type actin, and reduces flight ability in Drosophila (PS3; PMIDs: 15226407, 23294764). This variant has been reported in one proband, who has nemaline rods and thin filament accumulation present on muscle biopsy (PP4_Moderate; PMIDs: 11333380, 10838259). In summary, the variant meets criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PS3, PP4_Moderate, PM2_Supporting, PP2, PP3, (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA258142/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 3.03
• Publications: 4 publications found

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]

ACTA1 Gene-Disease associations (from GenCC):

• alpha-actinopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 2a, typical, autosomal dominant

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital myopathy with excess of thin filaments

  Inheritance: SD Classification: DEFINITIVE Submitted by: Illumina
• congenital myopathy 2c, severe infantile, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive scapulohumeroperoneal distal myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• rigid spine syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• zebra body myopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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.
• 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.414C>G	p.Ile138Met	missense_variant	Exon 3 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.414C>G	p.Ile138Met	missense_variant	Exon 3 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.414C>G	p.Ile138Met	missense_variant	Exon 3 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.279C>G	p.Ile93Met	missense_variant	Exon 2 of 6			ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Actin accumulation myopathy Pathogenic:2

Oct 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 138 of the ACTA1 protein (p.Ile138Met). 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 and/or clinical features of autosomal dominant ACTA1-related conditions (PMID: 10838259, 11333380; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as I136M. ClinVar contains an entry for this variant (Variation ID: 18286). 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 not expected to disrupt ACTA1 protein function. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 15226407, 23294764). This variant disrupts the p.Ile138 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been observed in individuals with ACTA1-related conditions (PMID: 11333380, 19562689), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Alpha-actinopathy Pathogenic:1

Aug 27, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_001100.4:c.414C>G in ACTA1 is a missense variant predicted to cause substitution of isoleucine by methionine at amino acid 138 (p.Ile138Met). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.799, which is above the threshold necessary to apply 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 addition, functional studies have demonstrated that this variant severely reduces co-polymerization compared to wild-type actin, and reduces flight ability in Drosophila (PS3; PMIDs: 15226407, 23294764). This variant has been reported in one proband, who has nemaline rods and thin filament accumulation present on muscle biopsy (PP4_Moderate; PMIDs: 11333380, 10838259). In summary, the variant meets criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PS3, PP4_Moderate, PM2_Supporting, PP2, PP3, (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		3.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N;.
REVEL	Pathogenic	0.80
Sift4G	Uncertain	0.051	T;T
Polyphen		0.14	B;.
Vest4		0.88
MutPred		0.80		Gain of phosphorylation at Y135 (P = 0.2011);Gain of phosphorylation at Y135 (P = 0.2011);
MVP		0.94
ClinPred		0.81	D
GERP RS		0.49
Varity_R		0.94
gMVP		0.91
Mutation Taster		=34/66	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909526; hg19: chr1-229568343;