rs730880723

Variant names:

• chr11-47346212-C-CT
• rs730880723
• NM_000256.3:c.1084dupA

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.1084dupA​(p.Ser362LysfsTer28) 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:3
• Conservation: PhyloP100: 7.63

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 11-47346212-C-CT is Pathogenic according to our data. Variant chr11-47346212-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 181159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1084dupA	p.Ser362LysfsTer28	frameshift_variant	Exon 12 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1084dupA	p.Ser362LysfsTer28	frameshift_variant	Exon 12 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1084dupA	p.Ser362LysfsTer28	frameshift_variant	Exon 11 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1084dupA		non_coding_transcript_exon_variant	Exon 12 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 04, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1084dupA pathogenic variant in the MYBPC3 gene been reported previously in one individual with HCM, and was absent from 307 control alleles (Wang J et al., 2014). Additionally, the c.1084dupA mutation was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant causes a shift in reading frame starting at codon Serine 362, changing it to a Lysine, and creating a premature stop codon at position 28 of the new reading frame, denoted p.Ser362LysfsX28. This 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, other frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM and dilated cardiomyopathy (DCM) (Stenson P et al., 2014). -

Jul 15, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. p.Ser362LysX28 (c.1084dupA) in the MYBPC3 gene. Given the strong evidence that frameshift variants in MYBPC3 are disease-causing we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant appears to be novel. This is a frame-shifting variant that creates a premature stop codon 5 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. 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). Furthermore, these types of variants in MYBPC3 are only very rarely seen in individuals without cardiomyopathy (Pan et al 2012). The variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of June 18, 2015). -

Hypertrophic cardiomyopathy Pathogenic:1

May 26, 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.Ser362Lysfs*28) 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: 25132132). This variant is also known as 1084_1085insA. ClinVar contains an entry for this variant (Variation ID: 181159). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730880723; hg19: chr11-47367763;