11-47349924-T-G

Variant names:

• chr11-47349924-T-G
• rs397516057
• NM_000256.3:c.506-2A>C

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.506-2A>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.20

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.6, offset of 7, new splice context is: cctgcctttgccggtggcAGcat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47349924-T-G is Pathogenic according to our data. Variant chr11-47349924-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 42765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47349924-T-G is described in Lovd as [Pathogenic]. Variant chr11-47349924-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.506-2A>C		splice_acceptor_variant, intron_variant	Intron 4 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.506-2A>C		splice_acceptor_variant, intron_variant	Intron 4 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.506-2A>C		splice_acceptor_variant, intron_variant	Intron 4 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.506-2A>C		splice_acceptor_variant, intron_variant	Intron 4 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448094 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719204

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Mar 01, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 506-2A>C variant in MYBPC3 has not been reported in the literature, but has been identified by our laboratory in 1 Caucasian individual with DCM (suspected burnt out HCM) and a family history of HCM, and segregated with disease in 2 aff ected relatives (LMM unpublished data). This variant occurs in the invariant reg ion (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice variants in MYBPC3 ar e established as pathogenic for HCM. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon the p redicted impact to the protein. -

Apr 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 4 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25078086, 28193612). ClinVar contains an entry for this variant (Variation ID: 42765). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 27834932). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Sep 23, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a A>C nucleotide substitution at the -2 position of intron 4 of the MYBPC3 gene. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 25740977, 27834932). This variant has been observed to segregate with disease in a family affected with hypertrophic cardiomyopathy (unpublished data by an external laboratory, Clinvar variation ID 42765). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A functional study using mRNA from the peripheral blood of an affected carrier has shown that this variant disrupts the canonical splice acceptor site and activates an alternative splice site, which results in a frameshift and premature protein truncation due to the loss of the first 7 nucleotides of exon 5 (PMID: 27834932). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.82		Position offset: -9
DS_AL_spliceai		0.99		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516057; hg19: chr11-47371475;