11-47343603-G-C

Position:

• chr11-47343603-G-C

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.1112C>G​(p.Pro371Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,130 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.59

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 Ig-like C2-type 2 (size 90) in uniprot entity MYPC3_HUMAN there are 21 pathogenic changes around while only 3 benign (88%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1112C>G	p.Pro371Arg	missense_variant	13/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1112C>G	p.Pro371Arg	missense_variant	13/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.1112C>G	p.Pro371Arg	missense_variant	12/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.1112C>G	p.Pro371Arg	missense_variant, NMD_transcript_variant	13/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460130 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 726260

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2019	This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 371 of the MYBPC3 protein (p.Pro371Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27600940, 20359594, 27483260). However, in at least one of these individuals pathogenic allele[s] were also identified in MYBPC3, which suggests that this c.1112C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 42505). 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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces proline with arginine at codon 371 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 20359594, 32228044, 32841044). All of these individuals also carried the pathogenic p.Lys1065Glnfs*12 truncation variant in the same gene (ClinVar Variation ID: 42693). This p.Pro371Arg variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 01, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro371Arg variant in MYBPC3 has been reported in 7 individuals with HCM (Girolami 2010, R ubattu 2016, Coppini 2014, LMM data), 3 of whom also carried the pathogenic p.Ly s1065fs variant. It was confirmed to be in cis (on the same allele) in two of th ese individuals, and both variants segregated with disease in 3 relatives, inclu ding 1 obligate carrier. The p.Lys1065fs variant has been detected several times in isolation (Girolami 2006*, Olivotto 2011*, Witjas-Paalberends 2013, LMM data ; *note that these manuscripts contain overlapping cohorts), suggesting that the p.Pro371Arg variant arose on its background in the compound heterozygotes. It i s unclear if the remaining 4 affected individuals also carry the p.Lys1065fs var iant. The p.Pro371Arg variant was absent from large population studies. Computat ional prediction tools and conservation analysis suggest that the p.Pro371Arg va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. In summary, while there is some suspicion for a patho genic role, the clinical significance of the p.Pro371Arg variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2021

Reported in conjunction with the c.3192dupC pathogenic variant in the MYBPC3 gene in multiple individuals in association with HCM referred for genetic testing at GeneDx and in published literature (Girolami et al., 2010; Olivotto et al., 2011; Calore et al., 2015; Rubattu et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 28986452, 27600940, 28679633, 25740977, 21835320, 20359594, 27483260) -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostCm	Uncertain	0.60
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.95
MutPred		0.82		Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);
MVP		0.88
MPC		0.85
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.78
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397515887; hg19: chr11-47365154;