rs397517072
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_005159.5(ACTC1):c.83C>T(p.Ala28Val) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A28T) has been classified as Uncertain significance.
Frequency
Consequence
NM_005159.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTC1 | ENST00000290378.6 | c.83C>T | p.Ala28Val | missense_variant | Exon 2 of 7 | 1 | NM_005159.5 | ENSP00000290378.4 | ||
ACTC1 | ENST00000560563.2 | n.189C>T | non_coding_transcript_exon_variant | Exon 2 of 6 | 2 | |||||
GJD2-DT | ENST00000503496.6 | n.300-15770G>A | intron_variant | Intron 2 of 2 | 2 | |||||
GJD2-DT | ENST00000671663.1 | n.95-15770G>A | intron_variant | Intron 1 of 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460966Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726816
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
The Ala28Val variant in ACTC has not been reported in the literature nor detecte d in large and broad populations (European and African American) sequenced by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), but has be en previously identified in one individual with HCM by our laboratory (unpublish ed data). Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala28Val variant may impact the protein, though this information is not predictive enough to determine patho genicity. Additional information is needed to fully assess the clinical signific ance of the Ala28Val variant. -
Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 28 of the ACTC1 protein (p.Ala28Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 50937). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 25611685, 37652022) -
Cardiovascular phenotype Uncertain:1
The c.83C>T (p.A28V) alteration is located in exon 2 (coding exon 1) of the ACTC1 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at