rs397516059

chr11-47349876-C-CA

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.551_552insT(p.Lys185GlufsTer56) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L184L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.22

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 11-47349876-C-CA is Pathogenic according to our data. Variant chr11-47349876-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 42771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.551_552insT	p.Lys185GlufsTer56	frameshift_variant	5/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.551_552insT	p.Lys185GlufsTer56	frameshift_variant	5/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.551_552insT	p.Lys185GlufsTer56	frameshift_variant	5/34	5		A2
MYBPC3	ENST00000544791.1	c.551_552insT	p.Lys185GlufsTer56	frameshift_variant, NMD_transcript_variant	5/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459754 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726036

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2020	Reported in a patient referred for HCM genetic testing in the published literature (Alfares et al., 2015; Walsh et al., 2017), and in several patients with HCM referred for genetic testing at GeneDx; Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42771; Landrum et al., 2016); Frameshift 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: 25611685, 27532257) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 19, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Lys185GlufsX56 Based on the data reviewed below we consider this variant as likely disease-causing, based on the type of variant and gene. This variant is located in exon 5 of the MYPBC3 gene. This is a frameshift variant. The c.551dupT variant causes a shift in the reading frame at codon Lysine185, changing it to an Glutamic acid and creates a premature Stop codon at position 56 of the new reading frame. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. This variant is novel. While this specific variant is novel, many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6.500 Caucasian and African American individuals (as of 1/3/14). This variant has not been reported in dbSNP or 1000Genomes. GeneDx did not report control data. -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change creates a premature translational stop signal (p.Lys185Glufs*56) 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 42771). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 13, 2015	The p.Lys185fs variant in MYBPC3 has been previously identified by our laborator y in three Caucasian adults with HCM. It has not been identified in large popula tion studies, though the ability of these studies to detect indels accurately ma y be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 185 and leads to a premature termination codon 56 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss-of-function of the M YBPC3 gene is an established disease mechanism in individuals with HCM. In summa ry, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) ba sed upon the predicted impact of the variant. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 10, 2021

- -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Apr 26, 2016

p.Lys185GlufsTer55 (CTGAAG>CT{T}GAAG) : c.551dupT in exon 5 of the MYBPC3 gene (NM_000256.3). The variant Lys185GlufsTer55 (p.K185EfsX55) in the MYBPC3 gene has not been reported to our knowledge. However, it was observed in more than ten (10) unrelated families tested for HCM by the Molecular Diagnostics Laboratory of the Montreal Heart Institute. It meets the following criteria of pathogenicity of the ACMG : PVS1 : The duplication of a thymidine at position 551 causes a change in the reading frame for 55 amino acids and leads to a stop codon resulting in a shortened protein of 81%. This variant is expected to result in an abnormal product : a truncated protein or loss of protein production from this allele through nonsense-mediated accelerated decay of the mRNA. PM2 :Lys185GlufsTer55 was not reported in ExAC database (more than 120,000 alleles) and was not observed in the populations of the 1000 Genome Project (more than 5000 individuals) neither in the populations of European and African American ancestry in the NHLBI Exome Sequencing Project (more than 6500 individuals). This means it is not a common benign variant in these populations. PP5 :The variant was the subject of two submissions in ClinVar: both in pathogenic category. In summary, Lys185GlufsTer55 in the MYBPC3 gene combines a very strong criteria of pathogenicity, a moderate criteria and a supporting criteria. It is interpreted as pathogenic variant. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2020

The c.551dupT pathogenic mutation, located in coding exon 5 of the MYBPC3 gene, results from a duplication of T at nucleotide position 551, causing a translational frameshift with a predicted alternate stop codon (p.K185Efs*56). This variant has been detected in a cohort referred for hypertrophic cardiomyopathy genetic testing (Walsh R et al. Genet Med. 2017 02;19:192-203). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516059; hg19: chr11-47371427;