NM_001100.4:c.553C>A

Variant names:

• chr1-229432333-G-T
• rs1064794287
• NM_001100.4:c.553C>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001100.4(ACTA1):​c.553C>A​(p.Arg185Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.86
• Publications: 8 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 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001100.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-229432333-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 464125.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the ACTA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 154 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.5292 (above the threshold of 3.09). Trascript score misZ: 6.088 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital myopathy with excess of thin filaments, congenital fiber-type disproportion myopathy, severe congenital nemaline myopathy, congenital myopathy 2a, typical, autosomal dominant, zebra body myopathy, alpha-actinopathy, rigid spine syndrome, progressive scapulohumeroperoneal distal myopathy, childhood-onset nemaline myopathy, typical nemaline myopathy, intermediate nemaline myopathy, congenital myopathy 2c, severe infantile, autosomal dominant.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-229432333-G-T is Pathogenic according to our data. Variant chr1-229432333-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.553C>A	p.Arg185Ser	missense_variant	Exon 4 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.553C>A	p.Arg185Ser	missense_variant	Exon 4 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.553C>A	p.Arg185Ser	missense_variant	Exon 4 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.418C>A	p.Arg140Ser	missense_variant	Exon 3 of 6			ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Dec 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 variant disrupts the p.Arg185 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10508519, 15226407, 24313005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 420099). This variant is also known as Arg183Ser. This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy (PMID: 12921789). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 185 of the ACTA1 protein (p.Arg185Ser). -

not provided Pathogenic:1

Feb 10, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R185S variant in the ACTA1 gene has been reported previously using alternate nomenclature R183S in the heterozygous state in an individual with severe nemaline myopathy (Sparrow et al., 2003). In addition, missense variants at this same codon (R185C, R185G, R185L) have also been reported in the heterozygous state in individuals with nemaline myopathy (Laing et al., 2009), and the R185C variant, reported as R183C using alternate nomenclature, has also been reported in the somatic mosaic state in an unaffected parent of two infants affected with severe nemaline myopathy (Nowak et al., 1999). The R185S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R185S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in neighboring codons (L180P, D181H, D181N, D181G, A183T, G184D, D186G) have been reported in the Human Gene Mutation Database in association with nemaline myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R185S as a pathogenic variant. -

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

Jan 16, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.94
Sift4G	Uncertain	0.059	T
Polyphen		0.99	D
Vest4		0.91
MutPred		0.91		Loss of methylation at R185 (P = 0.0934);
MVP		1.0
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		0.99
Mutation Taster		=6/94	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: rs1064794287; hg19: chr1-229568080;