11-47337450-G-T

Position:

• chr11-47337450-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000256.3(MYBPC3):​c.2543C>A​(p.Ala848Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2543C>A	p.Ala848Glu	missense_variant	25/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2543C>A	p.Ala848Glu	missense_variant	25/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2543C>A	p.Ala848Glu	missense_variant	24/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.*48C>A		3_prime_UTR_variant, NMD_transcript_variant	25/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 12, 2018	Variant MYBPC3 p.Ala848Glu c.2543C>A in exon 24 (NM_000256.3, hg19 chr11-47359001-G-T) SCICD classification variant of uncertain significance, probably disease causing We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: MYBPC3 missense variant, so need stronger evidence for pathogenicity. Sufficiently rare, need more cases or more segregation. Case data summary Reported in 4 presumably unrelated cases of HCM (not including the patient) and 1 case of DCM. There's weak segregation data. Please see below for a detailed review of case data. Population Data There is no variation at this codon in gnomAD. Metrics indicate adequate coverage (median coverage 66x for exomes, 33x for genomes). However, there is one individual listed with this variant in ExAC (1/4298 East Asian individuals (MAF 0.01163%), per varsome.com Case data: 1. HCM Melacini et al 2008 (lab report suggests likely redundant with Calore et al 2015) Variant seen in a 40yo male with HCM, obstruction, gradient, positive family history No data on segregation Recruited in Padua, Italy 2. HCM Meyer et al 2013 Variant seen in a patient with HCM No segregation data Recruitment: University of Marburg, Germany 3. HCM Ingles et al 2017 (presumably redundant with Burns et al 2017) Variant seen in a patient with HCM No data on segregation provided Recruited in Sidney, Australia 4. HCM Internal lab data, two affected family members have this variant. Other: 1. DCM Dal Ferro et al 2017 Variant seen in a patient with dilated cardiomyopathy. Insufficient data provided to assess whether patient has burntout HCM. Also carries another missense variant in MYBPC3 Authors classify p.Ala848Glu as likely pathogenic, rationale and data supporting classification not provided Recruited in Italy (Trieste Heart Muscle Disease Registry) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17643520, 25740977, 28416588, 31514951, 28408708, 28790153) -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Sep 18, 2018	This MYBPC3 Ala848Glu variant has been reported in 1 patient with HCM (Calore, et al., 2015) and 1 patient with DCM (Dal Ferro M, et al., 2017). It is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect, but no prediction is called by PolyPhen-HCM. We have identified this MYBPC3 Ala848Glu variant in 1 HCM patient (Ingles J, et al., 2017) and the variant was found to segregate to 3 affected family members (4 meiosis). Interestingly different variants at the same amino acid position (Ala848Gly and Ala848Glyfs*) have been reported in cardiomyopathies. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is rare in the general population (PM2), segregates with disease (PP1), in silico tools predict aberrant splicing to occur (PP3) and has been identified in a total of 3 probands (PS4_supporting), therefore we classify MYBPC3 Ala848Glu as a variant of "uncertain significance". -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala848 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 23816408, 25740977, 33782553), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 220872). This missense change has been observed in individuals with hypertrophic or dilated cardiomyopathy (PMID: 25740977, 28408708, 28416588; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 848 of the MYBPC3 protein (p.Ala848Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	4.7	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.5	D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.99
MVP		0.95
MPC		0.90
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730880569; hg19: chr11-47359001;