rs397516005
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000256.3(MYBPC3):c.3181C>T(p.Gln1061*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000812 in 1,600,156 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000256.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152264Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000836 AC: 2AN: 239364Hom.: 0 AF XY: 0.00000766 AC XY: 1AN XY: 130586
GnomAD4 exome AF: 0.00000622 AC: 9AN: 1447892Hom.: 0 Cov.: 32 AF XY: 0.00000971 AC XY: 7AN XY: 720702
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74394
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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This mutation is dentoed p.Gln1061Stop (CAG>TAG): c.3181 C>T in exon 29 of the MYBPC3 gene (NM_000256.3). The Gln1061Stop mutation in the MYBPC3 gene has been reported in association with HCM (Jaaskelainen P et al., 2002). Jaaskelainen et al. identified Gln1061Stop in 6 unrelated families with HCM from Finland, and it was not observed in 200 control chromosomes. This study reported this mutation co-segregated with HCM in multiple families and suggested Gln1061Stop may be a founder mutation in the Finnish population. Gln1061Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Gln1061Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). -
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Hypertrophic cardiomyopathy Pathogenic:3
The Gln1061X variant in MYBPC3 has been reported in the literature in six HCM pr obands, segregated in 12 affected or clinically suspicious relatives across five families and was absent from 328 healthy control chromosomes (Jaaskelaine 2002, Poutanen 2006). The families were all of Finnish ancestry, and haplotype analys is suggests that this variant could be a founder mutation in this population (Ja askelaine 2002). In addition, this variant has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS). Gln1061X is a nonsense variant leading to a premature termination co don at position 1061, which is predicted to lead to a truncated or absent protei n. Heterozygous loss of function of the MYBPC3 gene is an established disease me chanism in HCM patients. In summary, this variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studi es, absence from controls, and established disease mechanism. -
This sequence change creates a premature translational stop signal (p.Gln1061*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397516005, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12110947, 26267065, 27532257). It is commonly reported in individuals of Finnish ancestry (PMID: 22462493). ClinVar contains an entry for this variant (Variation ID: 42690). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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Cardiomyopathy Pathogenic:2
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This variant changes 1 nucleotide in exon 29 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported to segregate with hypertrophic cardiomyopathy in several Finnish families (PMID: 12110947) and is thought to be a founder mutation in the Finnish population (PMID: 22462493, 30775854). This variant has also been reported in several unrelated individuals from other ethnic populations affected with hypertrophic cardiomyopathy (PMID: 19666645, 27532257, 18803133). A study has shown this variant changes the morphology, calcium handling, and electrophysiological properties in cardiomyocytes derived from an individual affected with hypertrophic cardiomyopathy (PMID: 27057166). This variant has been identified in 4/270760 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Hypertrophic cardiomyopathy 4 Pathogenic:1
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Primary familial hypertrophic cardiomyopathy Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The p.Q1061* pathogenic mutation (also known as c.3181C>T), located in coding exon 29 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3181. This changes the amino acid from a glutamine to a stop codon within coding exon 29. This is the most prevalent mutation reported to cause hypertrophic cardiomyopathy in the Finnish population and has shown a founder effect (Jääskeläinen P et al. J Mol Med (Berl). 2002;80(7):412-22; Jääskeläinen P et al. Ann Med. 2013;45(1):85-90). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at