rs121912676
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_005159.5(ACTC1):c.268C>T(p.His90Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 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 Uncertain significance (★★).
Frequency
Consequence
NM_005159.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251492Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727248
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: ACTC1 c.268C>T (p.His90Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.268C>T has been reported in the literature in several individuals affected with Hypertrophic Cardiomyopathy (e.g. Morita_2008, Gomez_2017, Walsh_2017, Viswanathan_2017, Ho_2018). However, these reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. One publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in an increased calcium sensitivity (Teng_2019). Three ClinVar submitters have assessed the variant since 2014, and all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
The p.His90Tyr variant in ACTC1 has been reported in 3 individuals with HCM (Mor ita 2008, LMM unpublished data). This variant has also been identified in 1/6673 0 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs121912676). Computational prediction tools and conserv ation analysis suggest that the p.His90Tyr variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, the clinical significance of the p.His90Tyr variant is uncertain. -
Hypertrophic cardiomyopathy 11 Pathogenic:1
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Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Uncertain:1
This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 90 of the ACTC1 protein (p.His90Tyr). This variant is present in population databases (rs121912676, gnomAD 0.003%). This missense change has been observed in individual(s) with left ventricular hypertrophy or hypertrophic cardiomyopathy (PMID: 18403758, 27532257, 28356264, 29121657, 30297972, 36960733). ClinVar contains an entry for this variant (Variation ID: 18326). 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%. Experimental studies have shown that this missense change affects ACTC1 function (PMID: 31481237). 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
Inconclusive functional studies indicate that while this variant, reported as H88Y using alternate nomenclature, leads to increased calcium sensitivity of contraction, it resulted in similar activity and motility compared to wild type (PMID: 28972856, 31481237); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 28972856, 31481237, 28356264, 29121657, 18403758, 36960733, Valverde2021[CaseReport]) -
Hypertrophic cardiomyopathy Uncertain:1
This missense variant replaces histidine with tyrosine at codon 90 of the ACTC1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes increased calcium sensitivity in vitro (PMID: 31481237). This variant has been reported in six individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 27532257, 28356264, 29121657, ClinVar SCV000061992.5). This variant has been identified in 2/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
The c.268C>T (p.H90Y) alteration is located in exon 3 (coding exon 2) of the ACTC1 gene. This alteration results from a C to T substitution at nucleotide position 268, causing the histidine (H) at amino acid position 90 to be replaced by a tyrosine (Y). 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