rs397515992
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.2905C>T(p.Gln969*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000217 in 1,381,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000256.3 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYBPC3 | ENST00000545968.6 | c.2905C>T | p.Gln969* | stop_gained, splice_region_variant | Exon 27 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.2905C>T | p.Gln969* | stop_gained, splice_region_variant | Exon 26 of 34 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000217 AC: 3AN: 1381244Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2AN XY: 677732
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Identified in several patients referred for HCM genetic testing at GeneDx and found to segregate with disease in a relative of one proband; Reported in one patient with DCM (Hazebroek et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 26914223, 20359594, 22267749, 27373729, 9541104, 27532257, 15519027, 18533079, 21302287, 24111713, 26383716, 29540472, 30282064, 31006259, 29398688, 34137518, 24704860, 9541100, 33673806, 32880476, 32746448, 36203036, 34076677, 35653365) -
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MYBPC3: PVS1, PM2 -
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Hypertrophic cardiomyopathy Pathogenic:6
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This sequence change creates a premature translational stop signal (p.Gln969*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9541104, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42669). For these reasons, this variant has been classified as Pathogenic. -
This heterozygous nonsense variant in the MYBPC3 gene was identified in a male patient (53 years old) with familial hypertrophic cardiomyopathy -
This variant changes one nucleotide in exon 27 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 in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33673806, 34137518, 35653365, 36203036) and in a large family affected with familial hypertrophic cardiomyopathy (PMID: 9541104). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The Gln969X variant has been reported in the literature in at least 2 individual s with clinical features of HCM (Yu 1998, Van Driest 2004) and in our laboratory in three other individuals with HCM. The Gln969X variant leads to a premature s top at codon 969. This alteration is predicted to lead to a truncated or absent protein. Loss of function variants are an established mechanism of disease for t he MYBPC3 gene. It should be noted that this variant was seen in one family alo ng with a second likely pathogenic variant, suggesting that this variant may hav e a milder effect. In summary, the Gln969X variant is highly likely to be patho genic. -
Hypertrophic cardiomyopathy 4 Pathogenic:3
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PVS1, PS4, PM2, PP5 -
Cardiomyopathy Pathogenic:2
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This variant changes one nucleotide in exon 27 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 in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33673806, 34137518, 35653365, 36203036) and in a large family affected with familial hypertrophic cardiomyopathy (PMID: 9541104). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1
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Hypertrophic cardiomyopathy 1 Pathogenic:1
The MYBPC3 Gln969* variant has been observed in multiple unrelated HCM cases (Roncarati R, et al., 2011; Van Driest SL, et al., 2004; Yu B, et al., 1998) and absent in >150 controls (Van Driest SL, et al., 2004; Roncarati R, et al., 2011). Furthermore, this variant is absent from both the 1000 genomes project (http://www.1000genomes.org/) and Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified the MYBPC3 Gln969* variant in an HCM family where two additional variants in MYBPC3 (Arg668His; "uncertain significance") and MYH7 (Arg1079Gln; "uncertain significance") have also been observed in the family (Girolami F, et al., 2010). MYPBC3 Gln969* was identified in our HCM proband who carried the additional MYH7 Arg1079Gln variant. The proband's affected sister carries this MYBPC3 Gln969* as well as both additional MYBPC3 and MYH7 variants variants (Girolami F, et al., 2010). This MYBPC3 variant results in a premature stop codon in place of glutamine (Gln) at position 969 and predicted to result in a truncated protein. Given that loss-of-function variants in MYBPC3 are an established mechanism of disease in HCM, and that MYBPC3 Gln969* has been observed in other cases of familial HCM, we classify this variant as "pathogenic". -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at