rs397515975

Positions:

• chr11-47337435-CCG-CAGA

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.2556_2557delinsTCT​(p.Gly853LeufsTer31) 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: 32)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.57

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 11-47337436-CG-AGA is Pathogenic according to our data. Variant chr11-47337436-CG-AGA is described in ClinVar as [Pathogenic]. Clinvar id is 42639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2556_2557delinsTCT	p.Gly853LeufsTer31	frameshift_variant	25/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2556_2557delinsTCT	p.Gly853LeufsTer31	frameshift_variant	25/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2556_2557delinsTCT	p.Gly853LeufsTer31	frameshift_variant	24/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.*61_*62delinsTCT		3_prime_UTR_variant, NMD_transcript_variant	25/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

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

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	Jul 29, 2017	The c.2556_2557delCGinsTCT pathogenic variant in the MYBPC3 gene has been previously reported in multiple individuals in association with HCM, and has been denoted in published literature as c.2556_2557delinsTCT (p.Gly853fs), ins t, ggc>tgc (A851 fs/31), and delCG/insTCT 852, due to alternate nomenclature (Morner et al., 2003; Van Driest et al., 2004; Walsh et al., 2017). This variant was also shown to segregate with HCM in four affected relatives from one Swedish family, and haplotype analysis of three unrelated Swedish probands with HCM who harbored c.2556_2557delCGinsTCT suggests it may be a founder mutation in this population (Morner et al., 2003). Additionally, this variant is classified in ClinVar as a pathogenic variant by other clinical laboratories (ClinVar SCV000059157.4; SCV000264056.1; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon glycine 853, changing it to a leucine, and creating a premature stop codon at position 31 of the new reading frame, denoted p.Gly853LeufsX31. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, multiple other frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Finally, the c.2556_2557delCGinsTCT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2022	For these reasons, this variant has been classified as Pathogenic. This variant is also known as del CG, insTCT 852. This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12818575, 24510615, 27532257). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs752104988, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Gly853Leufs*31) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 07, 2018	The p.Gly853LeufsX31 variant in MYBPC3 has been identified in 7 Caucasian indivi duals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 af fected relatives from one family, including 1 affected obligate carrier (Morner 2003, Walsh 2017). In addition, this variant has been identified by our laborato ry in 2 adults with HCM, and was absent from large population studies, though th e ability of these studies to accurately detect indels may be limited. This vari ant is predicted to cause a frameshift, which alters the protein?s amino acid se quence beginning at position 853 and leads to a premature termination codon 31 a mino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this va riant meets criteria to be classified as pathogenic for HCM in an autosomal domi nant manner based upon the predicted impact on the protein, its absence from the general population, segregation studies and presence in multiple affected indiv iduals. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PP1, PM2. -

Cardiovascular phenotype Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 07, 2022	The c.2556_2557delCGinsTCT pathogenic mutation, located in coding exon 25 of the MYBPC3 gene, results from the deletion of two nucleotides and insertion of 3 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.G853Lfs*31). This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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	Mar 24, 2016	- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515975; hg19: chr11-47358987;