rs730880362

chr11-47351315-G-GCC

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.215_216insGG(p.Pro73AlafsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G72G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.06

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 11-47351315-G-GCC is Pathogenic according to our data. Variant chr11-47351315-G-GCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179537.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.215_216insGG	p.Pro73AlafsTer24	frameshift_variant	2/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.215_216insGG	p.Pro73AlafsTer24	frameshift_variant	2/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.215_216insGG	p.Pro73AlafsTer24	frameshift_variant	2/34	5		A2
MYBPC3	ENST00000544791.1	c.215_216insGG	p.Pro73AlafsTer24	frameshift_variant, NMD_transcript_variant	2/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 179537). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro73Alafs*24) 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	Feb 06, 2014	The Pro73fs variant in MYBPC3 has not been previously reported in individuals wi th cardiomyopathy. Data from large population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 73 and lead to a premature termination codon 24 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Heterozygous loss of function of the MY BPC3 gene is an established disease mechanism in individuals with HCM. In summar y, this variant meets our criteria to be classified as pathogenic (http://pcpgm. partners.org/LMM) based upon the predicted impact of the variant. -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 31, 2022

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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: rs730880362; hg19: chr11-47372866;