rs397515889

Variant names:

• chr11-47343546-TG-T
• rs397515889
• NM_000256.3:c.1168delC

Your query was ambiguous. Multiple possible variants found:

• chr11-47343546-TG-T
• chr11-47343546-TG-TGG

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.1168delC​(p.His390MetfsTer16) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). 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:6
• Conservation: PhyloP100: 5.39

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 11-47343546-TG-T is Pathogenic according to our data. Variant chr11-47343546-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343546-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1168delC	p.His390MetfsTer16	frameshift_variant	Exon 13 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1168delC	p.His390MetfsTer16	frameshift_variant	Exon 13 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1168delC	p.His390MetfsTer16	frameshift_variant	Exon 12 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1168delC		non_coding_transcript_exon_variant	Exon 13 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Dec 06, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in MYBPC3 is a frameshift variant predicted to create a premature stop codon, p.(His390Metfs*16), in biologically relevant exon 13/35 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 7493026, 9048664, 9562578, 17823372, 19574547, 18337725). Loss-of-function variants are a well-established cause of disease in exon 13 (ClinVar). This variant is absent from the population database gnomAD v4.1. This variant has been reported in at least two probands with hypertrophic cardiomyopathy (PMID: 26914223). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PM5_Supporting, PS4_Supporting -

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.His390Metfs*16) 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 individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 26914223). ClinVar contains an entry for this variant (Variation ID: 42508). For these reasons, this variant has been classified as Pathogenic. -

Apr 29, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26914223, 27532257, 11499719, 31006259, 34400558, 15519027) -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Oct 30, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1168delC (p.His390Metfs*16) variant in the MYBPC3 gene is predicted to result in a frameshift at codon 390, deleting the C-terminal 884 amino residues of the protein, likely causing loss or defect in protein function, which are known mechanisms for disease (PMID: 19574547). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 11499719, 26914223) and is absent from general population databases. Therefore, this c.1168delC (p.His390Metfs*16) variant in the MYBPC3 gene is classified as likely pathogenic. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Apr 30, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.1168delC (p.His390MetfsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Phe412X and p.Pro453fsX21). The variant was absent in 242438 control chromosomes. c.1168delC has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs397515889; hg19: chr11-47365097;