rs727503190

Positions:

• chr11-47338594-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000256.3(MYBPC3):​c.2234A>G​(p.Asp745Gly) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 7.67

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Ig-like C2-type 5 (size 126) in uniprot entity MYPC3_HUMAN there are 34 pathogenic changes around while only 4 benign (89%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2234A>G	p.Asp745Gly	missense_variant	23/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2234A>G	p.Asp745Gly	missense_variant	23/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2234A>G	p.Asp745Gly	missense_variant	22/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.2234A>G	p.Asp745Gly	missense_variant, NMD_transcript_variant	23/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Feb 20, 2020	The MYBPC3 Asp745Gly variant is absent from the he Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified the MYBPC3 Asp745Gly variant in an HCM proband where one additional MYBPC3 (Pro873His) variant of uncertain significance has also been observed (Ingles J., et al 2005). Recently we also identified a third variant (CSRP3 Arg146Cys) of "uncertain significance". Both MYBPC3 variants were found to segregate to an affected first degree family member. In silico tools (SIFT, PolyPhen-2, MutationTaster) support a deleterious role but is not sufficient enough to determine pathogenicity. We cannot rule out its possible role in disease but due to limited evidence, we class this variant as one of "uncertain significance". -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 02, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 26688216). 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: 30142). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16199542, 21839045, 27532257, 28679633, 30984009, 33782553). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 745 of the MYBPC3 protein (p.Asp745Gly). -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 20, 2022

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2022

The p.Asp745Gly variant in MYBPC3 has been reported in 4 individuals with hypertrophic cardiomyopathy (Ingles 2005 PMID: 16199542, Maron 2012 PMID: 21839045, Kresin 2019 PMID: 30984009, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 39098) and was absent from large population studies. In vitro functional studies provide some evidence that this variant impacts protein function, as this variant showed increased action potential in heart tissue from an HCM patient in 1 study, and displayed interference in protein folding in another (Nadvi 2016 PMID: 26688216, Flenner 2021 PMID: 33957110). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.0	D;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.045	D;D;D
Vest4		0.94
MVP		0.94
MPC		0.95
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503190; hg19: chr11-47360145;