1-229431527-G-A

Variant names:

• chr1-229431527-G-A
• rs1553255293
• NM_001100.4:c.1106C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4_Moderate PP4_Strong PP2 PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1106C>T (p.Pro369Leu) variant in ACTA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 369. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.922, 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). This variant has been reported in 4 probands with nemaline myopathy, 1 with nemaline rods (PS4_Moderate; PMIDs: 19562689, 26172852; ClinVar SCVs: SCV000589626.2, SCV002287790.1; Internal lab contributors: GeneDx, Invitae). At least one patient with this variant displayed nemaline rods and type 1 fiber predominance, which is highly specific for alpha-actinopathy (PP4_Moderate, PMID:26172852). The variant has been reported to segregate with autosomal dominant nemaline myopathy in 3 affected family members from 1 family (PP1; ClinVar SCV: SCV000589626.2, Internal lab contributors: GeneDx). 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: PP4_Strong, PS4_Moderate, PM2_Supporting, PP1, PP2, PP3. (Congenital Myopathies VCEP specifications version 2; 08/27/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA345144203/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.94
• Publications: 0 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

ENSG00000290037 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS4: 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.1106C>T	p.Pro369Leu	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.1106C>T	p.Pro369Leu	missense_variant	Exon 7 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.1028C>T	p.Pro343Leu	missense_variant	Exon 7 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.971C>T	p.Pro324Leu	missense_variant	Exon 6 of 6			ENSP00000508084.1
ENSG00000290037	ENST00000702606.2	n.162G>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:3

Revision: reviewed by expert panel

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Sep 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 369 of the ACTA1 protein (p.Pro369Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with autosomal dominant ACTA1-related conditions (PMID: 19562689, 26172852). ClinVar contains an entry for this variant (Variation ID: 431989). 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. 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. -

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.1106C>T (p.Pro369Leu) variant in ACTA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 369. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.922, 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). This variant has been reported in 4 probands with nemaline myopathy, 1 with nemaline rods (PS4_Moderate; PMIDs: 19562689, 26172852; ClinVar SCVs: SCV000589626.2, SCV002287790.1; Internal lab contributors: GeneDx, Invitae). At least one patient with this variant displayed nemaline rods and type 1 fiber predominance, which is highly specific for alpha-actinopathy (PP4_Moderate, PMID: 26172852). The variant has been reported to segregate with autosomal dominant nemaline myopathy in 3 affected family members from 1 family (PP1; ClinVar SCV: SCV000589626.2, Internal lab contributors: GeneDx). 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: PP4_Strong, PS4_Moderate, PM2_Supporting, PP1, PP2, PP3. (Congenital Myopathies VCEP specifications version 2; 08/27/2024) -

not provided Pathogenic:1

May 29, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26172852, 19562689) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.88		Loss of disorder (P = 0.0205);.;
MVP		0.99
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.90
gMVP		0.98
Mutation Taster		=0/100	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: rs1553255293; hg19: chr1-229567274;