rs752200396

Positions:

chr11-47338652-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3PP5

The NM_000256.3(MYBPC3):c.2176C>T(p.Arg726Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,442 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:9

Conservation

PhyloP100: 9.60

Variant links:

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]

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

PP5

Variant 11-47338652-G-A is Pathogenic according to our data. Variant chr11-47338652-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575705.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=9}. Variant chr11-47338652-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2176C>T	p.Arg726Cys	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 linkuse as main transcript	c.2176C>T	p.Arg726Cys	missense_variant	23/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2176C>T	p.Arg726Cys	missense_variant	22/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.2176C>T	p.Arg726Cys	missense_variant, NMD_transcript_variant	23/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000606

AC:

AN:

247584

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

134422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461276

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000105

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.0000765

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2024	Identified in a patient with HCM, a patient with sudden unexplained death (SUD), in a patient from the Jackson Heart Study cohort (PMID: 32917565, 19150014, 22958901); 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: 22958901, 22765922, 20594303, 33919104, 34426522, 32917565, 28356264, 19150014, 35885957) -
Likely pathogenic, flagged submission	clinical testing	Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	Feb 02, 2022	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2023	This missense variant replaces arginine with cysteine at codon 726 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22765922, 27930701), in an individual affected with noncompaction cardiomyopathy (PMID: 35885957), in an individual affected with Tetralogy of Fallot and multiple congenital anomalies (PMID: 35885957), and in an individual affected with sudden cardiac death (PMID: 32917565, 33919104). It has also been reported in an asymptomatic individual (PMID: 19150014). This variant has been identified in 16/278974 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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 726 of the MYBPC3 protein (p.Arg726Cys). This variant is present in population databases (rs752200396, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19150014). ClinVar contains an entry for this variant (Variation ID: 575705). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with cysteine at codon 726 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 22765922, 27930701), in an individual affected with noncompaction cardiomyopathy (PMID: 35885957), in an individual affected with Tetralogy of Fallot and multiple congenital anomalies (PMID: 35885957), and in an individual affected with sudden cardiac death (PMID: 32917565, 33919104). It has also been reported in an asymptomatic individual (PMID: 19150014). This variant has been identified in 16/278974 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. -

Left ventricular noncompaction 10

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud

Feb 02, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 14, 2023

Variant summary: MYBPC3 c.2176C>T (p.Arg726Cys) results in a non-conservative amino acid change located in the immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 247584 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (6.1e-05 vs 0.001), allowing no conclusion about variant significance. c.2176C>T has been reported in the literature in the heterozygous state in an individual affected with hypertrophic cardiomyopathy who was subsequently cited by others (Garcia-Castro_2009, Coto_2012, Gomez_2017), in two cases of sudden unexplained death, one of which was likely attributed to dilated cardiomyopathy (Sanchez_2016) and the other with no conclusive cardiac-related cause (Iglesias_2021), and in two unrelated individuals undergoing genetic testing for congenital abnormalities, one with noncompaction cardiomyopathy and one with multiple congenital abnormalities including Tetralogy of Fallot, both of whom inherited the variant from a presumably unaffected parent (Delea_2022). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22765922, 35885957, 19150014, 28356264, 33919104, 35629155, 27930701). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

Hypertrophic cardiomyopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant c.2176C>Tp.Arg726Cys in MYBPC3 gene has been reported in individuals affected with hypertrophic cardiomyopathy Sanchez et. al., 2016; Coto et. al., 2012, as well as in an asymptomatic individual García-Castro et. al., 2009. This variant has been reported in one case with sudden cardiac death Ripoll-Vera et. al., 2021. The p.Arg726Cys variant is novel not in any individuals in 1000 Genomes and has allele frequency of 0.006% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Uncertain Significance. The amino acid change p.Arg726Cys in MYBPC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 726 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance VUS. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2023

The p.R726C variant (also known as c.2176C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2176. The arginine at codon 726 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in individuals with varying phenotypes including hypertrophic cardiomyopathy, dilated cardiomyopathy, sudden unexplained death, congenital heart disease, and noncompaction cardiomyopathy (Coto E et al. J Transl Med, 2010 Jul;8:64; Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Iglesias M et al. J Clin Med, 2021 Apr;10; Delea M et al. Genes (Basel), 2022 Jun;13). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Benign

0.24

CardioboostCm

Benign

0.0029

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;T;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

0.014

MutationAssessor

Uncertain

2.4

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.4

D;.;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.89

MVP

0.94

MPC

0.92

ClinPred

0.61

GERP RS

5.4

Varity_R

0.45

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over