rs397516014

Positions:

• chr11-47333226-A-AC

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.3297_3298insG​(p.Tyr1100ValfsTer49) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G1099G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.892

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 11-47333226-A-AC is Pathogenic according to our data. Variant chr11-47333226-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 42702.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.3297_3298insG	p.Tyr1100ValfsTer49	frameshift_variant	30/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3297_3298insG	p.Tyr1100ValfsTer49	frameshift_variant	30/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3297_3298insG	p.Tyr1100ValfsTer49	frameshift_variant	29/34	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000138 AC: 3 AN: 216706 Hom.: 0 AF XY: 0.0000256 AC XY: 3 AN XY: 117106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000158

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000208 AC: 3 AN: 1444726 Hom.: 0 Cov.: 34 AF XY: 0.00000418 AC XY: 3 AN XY: 716926

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: 0.0000575

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 29, 2013	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.Tyr1100ValfsX49 (c. 3297dupG) in the MYBPC3 gene. We classify it as likely disease causing, based on the data reviewed below. The variant was re-reviewed February 17th, 2012. This variant is novel. The addition of Guanine at position 3297 causes a reading frame shift at codon 1100; as a result a premature stop codon is created 49 codons downstream. The amino acid sequence from codon 1100 to 1149 is changed, as well. The variant is expected to either cause a truncated MYBPC3 protein or a completely absent MYBPC3 protein due to nonsense-mediate 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). The variant has not been seen in a total of 5200 laboratory controls and publicly available general population samples. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes calls for MYBPC3 on ~5000 Caucasian and African-American individuals. Of note, there are no frameshift variants in that dataset. These if one nonsense variant, but it has been reported previously in association with HCM. There was no control data reported in the results. Upon request, GeneDx verbally provided control data on March 31st, 2011; the variant was not observed in 100 Caucasian control individuals (with high coverage) or 100 African American control individuals (with low coverage). -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 12, 2023	This sequence change creates a premature translational stop signal (p.Tyr1100Valfs*49) 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 present in population databases (rs397516014, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42702). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 13, 2012	The Tyr1100fs variant (MYBPC3) has not been reported in the literature but has b een identified in one individual with HCM (this individual's father) by our labo ratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 1100 and lead to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the MYBPC3 gene is an esta blished disease mechanism in HCM, which makes it highly likely that this variant is 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: rs397516014; hg19: chr11-47354777;