rs199728019

chr11-47341995-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_000256.3(MYBPC3):c.1786G>A(p.Gly596Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000048 in 1,561,638 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:2
• Conservation: PhyloP100: 7.53

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 4 (size 89) in uniprot entity MYPC3_HUMAN there are 43 pathogenic changes around while only 10 benign (81%) in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755
• BP6: Variant 11-47341995-C-T is Benign according to our data. Variant chr11-47341995-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42566.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1786G>A	p.Gly596Arg	missense_variant	18/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1786G>A	p.Gly596Arg	missense_variant	18/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1786G>A	p.Gly596Arg	missense_variant	17/34	5		A2
MYBPC3	ENST00000544791.1	c.1786G>A	p.Gly596Arg	missense_variant, NMD_transcript_variant	18/27	5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 20 AN: 172158 Hom.: 0 AF XY: 0.0000657 AC XY: 6 AN XY: 91262

Gnomad AFR exome AF: 0.000104

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000838

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.0000461 AC: 65 AN: 1409432 Hom.: 0 Cov.: 32 AF XY: 0.0000531 AC XY: 37 AN XY: 696172

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.000138

Gnomad4 ASJ exome AF: 0.00158

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000553

Gnomad4 OTH exome AF: 0.000205

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74358

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000590 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 21, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2018	proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 16, 2022	This missense variant replaces glycine with arginine at codon 596 of the MYBPC3 protein. Computational prediction suggests that this variant may have 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701), dilated cardiomyopathy (PMID: 32746448), or sudden death (PMID: 27930701). This variant has been identified in 21/203560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the elevated allele frequency in the general population suggests that this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	Reported in several unrelated individuals with HCM and one adult individual with unexplained sudden death in the published literature (Chung et al., 2007; Gruner et al., 2011; Alfares et al., 2015; Lopes et al., 2015; Sanchez et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 42566; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 26582918, 25558701, 28518168, 28166282, 25351510, 25611685, 21511876) -

Left ventricular noncompaction 10 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	Dec 07, 2022	The c.1786G>A (p.Gly596Arg) MYBPC3 variant has been reported in our laboratory in a 59-year-old female patient with a clinical diagnosis of non-compaction dilated cardiomyopathy, with severe left ventricular dysfunction and with defibrillator. A nephew who died of sudden death at 45 years of age. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701). This variant is present in population databases (gnomAD allele frequency 0.0001032). ClinVar contains an entry for this variant (Variation ID: 42566). In silico analysis (CADD, PolyPhen-2, MutationTaster, SIFT y Provean) supports that this missense variant has a deleterious effect on protein structure/function, but this prediction has not been confirmed by functional studies. In summary, the available evidence for c.1054A>G (p.Arg352Gly) TP63 variant is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 19, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Hypertrophic cardiomyopathy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 07, 2023	This missense variant replaces glycine with arginine at codon 596 of the MYBPC3 protein. Computational prediction suggests that this variant may have 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701), dilated cardiomyopathy (PMID: 32746448), or sudden death (PMID: 27930701). This variant has also been identified in 21/203560 chromosomes (14/9070 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the elevated allele frequency in the general population suggests that this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 31, 2014

- -

Hypertrophic cardiomyopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 19, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2020

The c.1786G>A (p.G596R) alteration is located in exon 18 (coding exon 18) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1786, causing the glycine (G) at amino acid position 596 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
CardioboostCm	Uncertain	0.25
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.2	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.5	D;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.89
MVP		0.95
MPC		0.90
ClinPred		0.74	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.88

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: rs199728019; hg19: chr11-47363546;