NM_000256.3:c.3767_3769delCCA
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000256.3(MYBPC3):c.3767_3769delCCA(p.Thr1256del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000256.3 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3767_3769delCCA | p.Thr1256del | disruptive_inframe_deletion | Exon 33 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.3767_3769delCCA | p.Thr1256del | disruptive_inframe_deletion | Exon 32 of 34 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461184Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726860
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
The p.Thr1256del variant in MYBPC3 has been previously reported in at least 5 individuals with HCM and segregated with disease in at least 6 affected relatives (including 2 obligate carriers) from 2 families (Bos 2014, Coppini 2014, Walsh 2017, Weissler-Snir 2017, LMM data). It has been reported in ClinVar (Variation ID: 42741), but was absent from large population studies. This variant is a deletion of one amino acid (Thr) at position 1256 and is not predicted to alter the protein reading frame. In summary, although additional studies are required to fully establish its clinical significance, the p.Thr1256del variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate; PP1_Moderate, PM2. -
This variant, c.3767_3769del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Thr1256del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24793961, 25524337, 27532257). ClinVar contains an entry for this variant (Variation ID: 42741). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not specified Pathogenic:1
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Cardiomyopathy Pathogenic:1
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not provided Pathogenic:1
In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25524337, 27532257, 28193612, 32527005, 31737537, 24793961, 39160446, 37652022) -
Hypertrophic cardiomyopathy 4 Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The c.3767_3769delCCA variant (also known as p.T1256del) is located in coding exon 33 of the MYBPC3 gene. This variant results from an in-frame CCA deletion at nucleotide positions 3767 to 3769. This results in the in-frame deletion of a threonine at codon 1256. This variant has been detected in several unrelated individuals with hypertrophic cardiomyopathy (HCM) and in several HCM cohorts, and has also been shown to segregate with disease (Coppini R et al. J. Am. Coll. Cardiol. 2014;64:2589-600; Walsh R et al. Genet. Med. 2016;epub; Weissler-Snir A et al. Circ Cardiovasc Imaging, 2017 Feb;10(2):pii: e005311; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9(Suppl 2):S292-S298; Lombardi M et al. J Clin Med, 2020 Jun;9(6); external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at