11-47347852-C-T

Position:

• chr11-47347852-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.821+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:2
• Conservation: PhyloP100: 6.19

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47347852-C-T is Pathogenic according to our data. Variant chr11-47347852-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47347852-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-47347852-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.821+5G>A		splice_region_variant, intron_variant		ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.821+5G>A		splice_region_variant, intron_variant		5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.821+5G>A		splice_region_variant, intron_variant		5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.821+5G>A		splice_region_variant, intron_variant		5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1411554 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 697410

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Jan 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1997	- -
Uncertain significance, flagged submission	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 14, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 16, 2022	PM2, PP3, PP5 -

Hypertrophic cardiomyopathy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2014	The 821+5G>A variant in MYBPC3 has been reported in 2 individuals with HCM, was absent from 400 control chromosomes, and segregated with disease in 4 affected r elatives from 1 family (Carrier 1997, Richard 2003). In addition, this variant h as been identified by our laboratory in 2 Caucasian adults with HCM. This varian t is located in the 5' splice region and in vitro studies indicate this variant leads to aberrant splicing which is predicted to result in a truncated or absent protein (Carrier 1997, Flavigny 1999, Flavigny 2003). In summary, segregation a nd in vitro studies suggest that this variant is likely pathogenic, though addit ional studies are required to fully establish its clinical significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2023	This sequence change falls in intron 7 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 9048664, 12707239, 23140321). This variant is also known as IVS7+5G>A. ClinVar contains an entry for this variant (Variation ID: 42796). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (PMID: 9048664). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2021	Not observed in large population cohorts (Lek et al., 2016); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Published functional studies demonstrate that this variant leads to exon skipping and premature truncation (Carrier et al., 1997; Flavigny et al., 1999; Ito et al., 2017); Reported in ClinVar (ClinVar Variant ID# 42796; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31513939, 24721642, 28679633, 10610770, 9048664, 20624503, 12707239, 14613868, 30847666, 33673806) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 04, 2017	- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Feb 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516077; hg19: chr11-47369403;