1-229433007-C-A

Variant names:

• chr1-229433007-C-A
• rs1553255521
• NM_001100.4:c.109G>T

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 1 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: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.109G>T	p.Val37Leu	missense_variant	Exon 2 of 7	ENST00000366684.7	NP_001091.1

Ensembl

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

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

May 27, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has been reported in an individual affected with nemaline myopathy (PMID: 19562689, 23394784). 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. This variant is not present in population databases (ExAC no frequency). 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. 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"). -

Apr 11, 2020

Pediatric Department, Peking University First Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: provider interpretation

- -

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 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

Jan 12, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		7.9
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553255521; hg19: chr1-229568754;