rs397516075

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000256.3(MYBPC3):c.814C>T(p.Arg272Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,567,620 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 1 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 3.53

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 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.814C>T	p.Arg272Cys	missense_variant	Exon 7 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.814C>T	p.Arg272Cys	missense_variant	Exon 7 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.814C>T	p.Arg272Cys	missense_variant	Exon 7 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.814C>T		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000452

AC:

AN:

176988

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

94920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000376

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:

0.0000939

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000678

AC:

AN:

1415468

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

699738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000533

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:

0.0000854

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000765

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the MYBPC3 protein (p.Arg272Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dilated cardiomyopathy (DCM), peripartum cardiomyopathy, or hypertrophic cardiomyopathy (HCM) (PMID: 16715312, 20458009, 20624503, 20800588, 23140321, 27532257, 28771489, 37652022). ClinVar contains an entry for this variant (Variation ID: 42794). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYBPC3 function (PMID: 18957093). 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. -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 272 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). An experimental study has suggested that this variant may affect phosphorylation of the MyBP-C motif (PMID: 18957093). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 16715312), in an individual affected with peripartum cardiomyopathy (PMID: 20458009), and in four individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27532257, 28771489). One of these individuals also carried a pathogenic p.Arg302Gln variant in the PRKAG2 gene, suggesting that this MYBPC3 variant may not have been the primary cause of disease in that individual (PMID: 28771489). This variant has been identified in 9/208346 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. -

not specified

Uncertain:1

Apr 01, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg272Cys variant in MYBPC3 has been reported in 5 individuals with hypertrophic cardiomyopathy (HCM) and in at least 3 individuals with dilated cardiomyopathy (DCM) as well as 1 possibly affected family member with DCM (Zeller 2006 PMID:16715312, Ehlermann 2008 PMID:18957093, Hershberger PMID:20215591, Millat 2010 PMID:20624503, Morales 2010 PMID: 20458009, Terilinck PMID:23140321, Walsh 2017 PMID: 27532257, Mademonet-Soler PMID:28771489, LMM data). One of the individuals with HCM (age 24) also carried a pathogenic variant in another HCM causing gene (Mademonet-Soler PMID: 28771489). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42794) and has been identified in 0.008% (7/89912) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org. Preliminary results from an vitro functional study provide some evidence that this variant decreases phosphorylation compared to the wild type (Ehlermann 2008 PMID:18957093); however, the clinical significance of this is uncertain. 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: PP3. -

Cardiomyopathy

Uncertain:1

Nov 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 272 of the MYBPC3 protein. Computational prediction tool indicates this variant may have an uncertain impact on protein structure and function. An experimental study has suggested that this variant may affect phosphorylation of the MyBP-C motif (PMID: 18957093). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 16715312), in an individual affected with peripartum cardiomyopathy (PMID: 20458009), and in four individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27532257, 28771489). One of these individuals also carried a pathogenic p.Arg302Gln variant in the PRKAG2 gene, suggesting that this MYBPC3 variant may not have been the primary cause of disease in that individual (PMID: 28771489). This variant has been identified in 9/208346 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. -

not provided

Uncertain:1

Nov 13, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.(R272C) variant has been reported previously in association with DCM, HCM, and in one case of peri-partum cardiomyopathy (PMID: 16715312, 18957093, 20215591, 20458009, 20624503, 23140321); however, informative segregation and functional data were not provided.; 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: 27896284, 20458009, 28771489, 23140321, 27532257, 22337857, 20215591, 20624503, 18957093, 29687901, 20800588, 16715312) -

Long QT syndrome

Uncertain:1

May 08, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy

Uncertain:1

Genetics and Genomics Program, Sidra Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hypertrophic cardiomyopathy 4

Uncertain:1

Oct 17, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYBPC3-related disorder (PMID: 16715312, 27532257). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Cardiovascular phenotype

Uncertain:1

Aug 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.814C>T (p.R272C) alteration is located in exon 7 (coding exon 7) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 814, causing the arginine (R) at amino acid position 272 to be replaced by a cysteine (C). 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

Benign

0.33

CardioboostCm

Uncertain

0.19

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.92

MVP

0.87

MPC

0.95

ClinPred

0.77

GERP RS

5.5

Varity_R

0.37

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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