1-229431579-A-G

Position:

• chr1-229431579-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM6 PP2 PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_001100.3:c.1054T>C in ACTA1 is a missense variant predicted to cause substitution of serine by proline at amino acid 352 (p.Ser352Pro). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.942, 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). There is no published data on this variant, however Invitae has reported the variant in three unrelated probands, two of which presented with hypotonia (PS4_Supporting; SCV000638354.5). In addition, one of these probands had a de novo occurrence of the variant with parental relationships unconfirmed (PM6). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PM2_Supporting, PP2, PP3, PS4_Supporting, PM6 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA345144596/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.27

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 Likely_pathogenic. Variant got 6 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.
• PM6: 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.1054T>C	p.Ser352Pro	missense_variant	7/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.1054T>C	p.Ser352Pro	missense_variant	7/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000684723.1	c.919T>C	p.Ser307Pro	missense_variant	6/6			ENSP00000508084.1
ACTA1	ENST00000366683.4	c.991-15T>C		intron_variant		5		ENSP00000355644.4
ENSG00000290037	ENST00000702606.1	n.214A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 464113). This missense change has been observed in individual(s) with congenital myopathy (Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 352 of the ACTA1 protein (p.Ser352Pro). -

Alpha-actinopathy Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 27, 2024

The variant NM_001100.3:c.1054T>C in ACTA1 is a missense variant predicted to cause substitution of serine by proline at amino acid 352 (p.Ser352Pro). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.942, 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). There is no published data on this variant, however Invitae has reported the variant in three unrelated probands, two of which presented with hypotonia (PS4_Supporting; SCV000638354.5). In addition, one of these probands had a de novo occurrence of the variant with parental relationships unconfirmed (PM6). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PM2_Supporting, PP2, PP3, PS4_Supporting, PM6 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.5	N;.
REVEL	Pathogenic	0.94
Sift4G	Benign	0.082	T;T
Polyphen		0.90	P;.
Vest4		0.82
MutPred		0.76		Loss of MoRF binding (P = 0.14);.;
MVP		1.0
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.97
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: rs1553255301; hg19: chr1-229567326;