rs727504399
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5
The NM_005159.5(ACTC1):c.76G>A(p.Asp26Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005159.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTC1 | ENST00000290378.6 | c.76G>A | p.Asp26Asn | missense_variant | Exon 2 of 7 | 1 | NM_005159.5 | ENSP00000290378.4 | ||
ACTC1 | ENST00000560563.2 | n.182G>A | non_coding_transcript_exon_variant | Exon 2 of 6 | 2 | |||||
GJD2-DT | ENST00000503496.6 | n.300-15763C>T | intron_variant | Intron 2 of 2 | 2 | |||||
GJD2-DT | ENST00000671663.1 | n.95-15763C>T | intron_variant | Intron 1 of 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461138Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726892
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Pathogenic:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 26 of the ACTC1 protein (p.Asp26Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ACTC1-related conditions and hypertrophic cardiomyopathy (PMID: 27532257, 30600190). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177917). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTC1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Hypertrophic cardiomyopathy 11 Pathogenic:1
The c.76G>A (p.Asp26Asn) ACTC1 variant has been reported in our laboratory in a 67-year-old patient with diagnosis of hypertrophic cardiomyopathy. Father (sudden death 30y) and paternal grandmother (sudden death 50y). In our Hospital, it has been reported in another family with hypertrophic cardiomyopathy with positive segregation. This variant is present in population databases (gnomAD allele frequency 0.0000006198). This variant has been previously reported in a patients with hypertrophic cardiomyopathy [PMID 27532257, 30600190]. ClinVar contains an entry for this variant (Variation ID: 117917). In silico analysis (CADD, Revel) supports that this missense variant has a deleterious effect on protein structure/function. In summary, c.76G>A (p.Asp26Asn) ACTC1 variant meets our criteria to be classified as pathogenic based upon its absence from controls, computational evidence of pathogenicity in this family and having been widely described in relation to the patient´s phenotype. -
not specified Uncertain:1
proposed classification - variant undergoing re-assessment, contact laboratory -
not provided Uncertain:1
p.Asp26Asn (GAT>AAT):c.76 G>A in exon 2 of the ACTC1 gene (NM_005159.4). The Asp26Asn variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp26Asn results in a semi-conservative amino acid substitution of a negatively charged Aspartic acid residue with a neutral, polar Asparagine residue at a position that is conserved across species. In silico analysis predicts Asp26Asn is probably damaging to the protein structure/function. Furthermore, the NHLBI ESP Exome Variant Server reports Asp26Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in surrounding residues of the ACTC1 gene have been reported in association with HCM, suggesting this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Asp26Asn is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at