rs397516022

chr11-47332704-T-Achr11-47332704-T-Cchr11-47332704-T-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3491-2A>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,120 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MYBPC3 NM_000256.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.66

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 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47332704-T-A is Pathogenic according to our data. Variant chr11-47332704-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332704-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3491-2A>T		splice_acceptor_variant		ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3491-2A>T		splice_acceptor_variant		5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3491-2A>T		splice_acceptor_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 16, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 15, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2018	The c.3491-2 A>T variant in the MYBPC3 gene has been reported previously in association with hypertrophic cardiomyopathy (HCM) (Alfares et al., 2015). This variant destroys the canonical splice acceptor site in intron 31 and is predicted to cause abnormal gene splicing. Other splice site variants in the MYBPC3 gene, including a different variant affecting the same acceptor site (c.3491-1 G>A), have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.3491-2 A>T variant is not observed in large population cohorts (Lek et al., 2016). -

Hypertrophic cardiomyopathy 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 12, 2023	The MYBPC3 c.3491-2A>T variant results in a substitution at the consensus splice acceptor site, which may result in splicing defects. This variant has been reported in at least five unrelated individuals with hypertrophic cardiomyopathy (PMID: 25611685; PMID: 30282064; PMID: 31006259). This variant has been classified as pathogenic by at least three submitters in ClinVar. This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Additionally, other substitutions at this same splice acceptor junction, such as c.3491-1G>A and c.3491-3C>G, have been reported in other patients with hypertrophic cardiomyopathy (PMID: 23283745; PMID: 30645170). Based on the available evidence, the c.3491-2A>T variant is classified as pathogenic for hypertrophic cardiomyopathy. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 08, 2023	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2023	This sequence change affects an acceptor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 25611685, 27532257, 30282064). ClinVar contains an entry for this variant (Variation ID: 42717). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	Apr 18, 2012	The 3491-2A>T variant (MYBPC3) has been identified in three individuals with HCM tested by our laboratory. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing lea ding to an abnormal or absent protein. Heterozygous loss of function of the MYBP C3 gene is an established disease mechanism in HCM. In summary, this variant mee ts our criteria for pathogenicity (http://pcpgm.partners.org/LMM). -

Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	31
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		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: rs397516022; hg19: chr11-47354255;