rs397515894

Positions:

• chr11-47343135-CAA-C
• chr11-47343135-CAA-CAAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1235_1236delTT​(p.Phe412fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.83

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47343135-CAA-C is Pathogenic according to our data. Variant chr11-47343135-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 42514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343135-CAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1235_1236delTT	p.Phe412fs	frameshift_variant	15/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1235_1236delTT	p.Phe412fs	frameshift_variant	15/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1235_1236delTT	p.Phe412fs	frameshift_variant	14/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1235_1236delTT		non_coding_transcript_exon_variant	15/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2023	Identified in multiple patients with HCM referred to GeneDx and in published literature (Richard et al., 2003; Van Driest et al., 2004; Ehlermann et al., 2008; Berge et al., 2014; Kapplinger et al., 2014; Viswanathan et al., 2017); of note, this variant is also described as del TT[10512-10513] and I411 fs/0; 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; Not observed in large population cohorts (gnomAD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42514; ClinVar); This variant is associated with the following publications: (PMID: 24111713, 24510615, 12707239, 18957093, 15519027, 29121657, 35653365) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 19, 2023	PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2019	The p.Phe412X variant in MYBPC3 has been reported in >3 individuals with HCM (Richard 2003, Van Driest 2004, LMM data) and was absent from large population studies. It has also been reported in ClinVar (Variant ID: 42514). This variant is a deletion of 2 bases resulting in a premature termination codon at position 412, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, the p.Phe412X variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change creates a premature translational stop signal (p.Phe412*) 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: 12707239, 18957093, 24111713, 24510615). ClinVar contains an entry for this variant (Variation ID: 42514). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2023	The c.1235_1236delTT pathogenic mutation, located in coding exon 15 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 1235 to 1236, causing a translational frameshift with a predicted alternate stop codon (p.F412*). This alteration, also referred to as del TT[10512-10513] or I411 fs/0, has been reported in individuals with hypertrophic cardiomyopathy (Richard P et al. Circulation, 2003 May;107:2227-32; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2016	Variant summary: The MYBPC3 c.1235_1236delTT (p.Phe412Terfs) variant is a frameshift mutation predicted to cause loss of normal protein function due to production of a truncated protein or by the absence of the protein product due to nonsense-mediated mRNA decay. Mutation taster predicts a damaging outcome for this variant. It was not found in 102952 control chromosomes while it was reported in several patients with HCM from the literature. In one family, the variant co-segregated with disease, indicating pathogenicity. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu667fs), further supporting a deleterious outcome. In addition, clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 13, 2020

This variant deletes 2 nucleotides in exon 15 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals and in a family affected with hypertrophic cardiomyopathy or referred for hypertrophic cardiomyopathy genetic testing (PMID: 12707239, 18957093, 24111713, 24510615). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs397515894; hg19: chr11-47364686;