rs397516040

Positions:

• chr11-47332116-TTGG-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.67

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]

ACMG classification

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
MYBPC3	NM_000256.3	c.3767_3769delCCA	p.Thr1256del	disruptive_inframe_deletion	33/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3767_3769delCCA	p.Thr1256del	disruptive_inframe_deletion	33/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3767_3769delCCA	p.Thr1256del	disruptive_inframe_deletion	32/34	5		ENSP00000382193.2

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

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

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2019	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	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

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 16, 2017

- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 18, 2018

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2020

Reported 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 submitter

clinical testing

MGZ Medical Genetics Center

Jul 20, 2021

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

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: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs397516040; hg19: chr11-47353667;