1-229431994-C-G

Variant names:

• chr1-229431994-C-G
• rs121909525
• NM_001100.4:c.808G>C

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.808G>C​(p.Gly270Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G270C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 NM_001100.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.93
• Publications: 6 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 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr1-229431994-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18285.Status of the report is no_assertion_criteria_provided, 0 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-229431994-C-G is Pathogenic according to our data. Variant chr1-229431994-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 228243.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.808G>C	p.Gly270Arg	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.808G>C	p.Gly270Arg	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.808G>C	p.Gly270Arg	missense_variant, splice_region_variant	Exon 5 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.673G>C	p.Gly225Arg	missense_variant, splice_region_variant	Exon 4 of 6			ENSP00000508084.1
ENSG00000290037	ENST00000702606.2	n.*133C>G		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Jun 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with arginine at codon 270 of the ACTA1 protein (p.Gly270Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 5 of the ACTA1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with nemaline myopathy (PMID: 12921789, 15226407, 21514153). This variant is also known as Gly268Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 228243). Experimental studies do not agree on the impact of this missense change. One study reports this sequence change behaves similar to wild type (PMID: 17227580) while another study reports this change impairs polymerization (PMID: 15226407). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Gly270Cys, also reported as p.Gly268Cys) has been determined to be pathogenic (PMID: 12921789, 15226407, 15198992, 11333380). This suggests that the glycine residue is critical for ACTA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. -

Neuromuscular disease Pathogenic:1

Dec 21, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly270Arg variant in ACTA1 (also known as p.Gly268Arg) has been previously reported in at least 4 individuals with nemaline myopathy, including 2 confirme d de novo occurrences (Sparrow 2003, Laing 2009, LMM data). It was absent from l arge population studies. Several different variants at this position have occurr ed de novo in children with nemaline myopathy (p.Gly270Asp, p.Gly270Cys, and p.G ly270Ser; reported as p.Gly268Asp, p.Gly268Cys, and p.Gly268Ser; Ilkovski 2001, Graziano 2004, Ohlsson 2004, Laing 2009), supporting that changes at this codon are not tolerated. In vitro functional studies and structural analysis of the pr otein support an impact on protein function (Costa 2004, Bathe 2007, von der Eck en 2015). In addition, this variant is located last three bases of the exon, whi ch is part of the 5? splice region and computational tools suggest a possible im pact to splicing. In summary, this variant meets criteria to be classified as pa thogenic for autosomal dominant nemaline myopathy. ACMG/AMP Criteria applied: P M5_Strong, PM6_Strong, PS4_Moderate, PS3_Moderate, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		5.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.98
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.91		Loss of glycosylation at S267 (P = 0.0472);
MVP		1.0
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.030		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: rs121909525; hg19: chr1-229567741;