rs397515973

Positions:

• chr11-47337454-AGACGC-A

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.2534_2538del​(p.Arg845LeufsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,120 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. R845R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.95

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 11-47337454-AGACGC-A is Pathogenic according to our data. Variant chr11-47337454-AGACGC-A is described in ClinVar as [Pathogenic]. Clinvar id is 42635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337454-AGACGC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2534_2538del	p.Arg845LeufsTer37	frameshift_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2534_2538del	p.Arg845LeufsTer37	frameshift_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2534_2538del	p.Arg845LeufsTer37	frameshift_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.*39_*43del		3_prime_UTR_variant, NMD_transcript_variant	25/27	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461120 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726830

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2012	A deletion of 5 nucleotides in exon 25 of the MYBPC3 gene. The normal sequence with the bases that are deleted in braces is: ATGC{GCGTC}TACG. This mutation is denoted c.2534_2538delGCGTC at the cDNA level or at the protein level as p.Arg845LeufsX37. The c.2534_2538delGCGTC mutation in the MYBPC3 gene has been reported previously in one individual with HCM and it was not present in 200 control chromosomes (Richard P, 2003). The c.2534_2538delGCGTC mutation causes a shift in reading frame starting at codon Arginine 845, changing it to a Leucine, and creates a premature stop codon at position 37 of the new reading frame. This mutation is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. The variant is found in HCM panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 11, 2022	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 21, 2011	The Arg845fs variant has been reported in the literature in 1 family with HCM, w as absent from 400 control chromosomes, and segregated with disease in 5 affecte d family members (Carrier 1997, Richard 2003). In addition, this variant is pre dicted to cause a frameshift, which alters the protein's amino acid sequence beg inning at codon 845 and leads to a premature stop codon 37 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. Loss of function is an established mechanism of disease for the MYBPC3 gene. Th erefore, the Arg845fs variant meets our criteria for pathogenicity (http://pcpgm .partners.org/lmm) based on segregation, absence in controls, and impact of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 06, 2022	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg845Leufs*37) 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 premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9048664, 27532257). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42635). This variant is also known as c.2566_2570del. -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1997

- -

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: rs397515973; hg19: chr11-47359005;