rs371488302

Positions:

• chr11-47337792-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP5 BP4

The NM_000256.3(MYBPC3):​c.2311G>A​(p.Val771Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000419 in 1,550,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:7
• Conservation: PhyloP100: 4.74

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 2 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
• PP5: Variant 11-47337792-C-T is Pathogenic according to our data. Variant chr11-47337792-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161308.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=6}. Variant chr11-47337792-C-T is described in Lovd as [Pathogenic]. Variant chr11-47337792-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.37846848). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2311G>A	p.Val771Met	missense_variant, splice_region_variant	24/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2311G>A	p.Val771Met	missense_variant, splice_region_variant	24/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2311G>A	p.Val771Met	missense_variant, splice_region_variant	23/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2311G>A		splice_region_variant, non_coding_transcript_exon_variant	24/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152102 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000396 AC: 6 AN: 151534 Hom.: 0 AF XY: 0.0000248 AC XY: 2 AN XY: 80654

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.0000429 AC: 60 AN: 1398740 Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 28 AN XY: 689892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.0000278

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74410

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.000126 AC: 1

ExAC AF: 0.0000340 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Left ventricular noncompaction 10 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 14, 2023	- -

Hypertrophic cardiomyopathy 4 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 14, 2023	- -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 771 of the MYBPC3 protein (p.Val771Met). This variant is present in population databases (rs371488302, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic or dilated cardiomyopathy (PMID: 16004897, 21302287, 23233322, 25740977, 27600940, 28356264, 28679633, 28771489, 33782553). ClinVar contains an entry for this variant (Variation ID: 161308). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 10, 2024	This missense variant replaces valine with methionine at codon 771 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 28771489, 28356264, 27600940, 25740977, 25524337, 23233322, 21302287, 18533079, 16004897). Some of these individuals also carried a pathogenic variant in the same gene that could explain the observed phenotype (PMID: 25740977, 27600940, 28356264). It has also been reported in an individual affected with myocardial fibrosis (PMID: 35265679). This variant has been identified in 6/151534 chromosomes 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. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2015

p.Val771Met (GTG>ATG): c.2311 G>A in exon 24 of the MYBPC3 gene (NM_000256.3). The Val771Met mutation in the MYBPC3 gene has been reported previously in one Spanish individual diagnosed with HCM in childhood, and was absent from 100 ethnically-matched control individuals in this study (Garcia-Castro M et al., 2004). This individual's mother and sibling also harbored Val771Met. The mother was found to have left ventricular hypertrophy while the sibling had a normal echocardiogram. Subsequently, Val771Met was reported in one Egyptian individual with HCM who also harbored the Leu267Val mutation in the MYH7 gene (Kassem H et al., 2013). The Val771 residue is completely conserved across species, and in silico analysis predicts Val771Met is damaging to protein structure/function. Val771Met was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In summary, Val771Met in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s). -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 21, 2019

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 30, 2023

This missense variant replaces valine with methionine at codon 771 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 28771489, 28356264, 27600940, 25740977, 25524337, 23233322, 21302287, 18533079, 16004897). Some of these individuals also carried a pathogenic variant in the same gene that could explain the observed phenotype (PMID: 25740977, 27600940, 28356264). It has also been reported in an individual affected with myocardial fibrosis (PMID: 35265679). This variant has been identified in 6/151534 chromosomes 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. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 25, 2014

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The p.V771M variant (also known as c.2311G>A), located in coding exon 24 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2311. The valine at codon 771 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in several hypertrophic cardiomyopathy (HCM) cohorts; however, in several of the individuals noted in the cohorts additional alterations in genes associated with HCM were also reported (Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; Roncarati R et al. J Cell Physiol, 2011 Nov;226:2894-900; Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80; Calore C et al. J Med Genet, 2015 May;52:338-47; Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
CardioboostCm	Uncertain	0.54
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.90
MVP		0.81
MPC		0.67
ClinPred		0.27	T
GERP RS		3.8
Varity_R		0.35
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs371488302; hg19: chr11-47359343;