rs397516040

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

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.67
Variant links:
Genes affected
MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a domain Ig-like C2-type 7 (size 93) in uniprot entity MYPC3_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000256.3
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000256.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 11-47332116-TTGG-T is Pathogenic according to our data. Variant chr11-47332116-TTGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332116-TTGG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.3767_3769delCCA p.Thr1256del disruptive_inframe_deletion 33/35 ENST00000545968.6 NP_000247.2 Q14896-1A5YM48

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.3767_3769delCCA p.Thr1256del disruptive_inframe_deletion 33/355 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.3767_3769delCCA p.Thr1256del disruptive_inframe_deletion 32/345 ENSP00000382193.2 A8MXZ9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461184
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
726860
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000151

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2023This 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. -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 14, 2019The 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. -
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 16, 2017- -
Cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJan 18, 2018- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxOct 09, 2020Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 42741; Landrum et al., 2016); In-frame deletion of 1 amino acids in a non-repeat region; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25524337, 24793961, 27532257, 28193612, 32527005, 31737537) -
Hypertrophic cardiomyopathy 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 20, 2021- -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 24, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397516040; hg19: chr11-47353667; API