Variant rs397515994 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2938C>T	p.Arg980Cys	missense_variant	28/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2938C>T	p.Arg980Cys	missense_variant	28/35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2938C>T	p.Arg980Cys	missense_variant	27/34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.0000223

AC:

AN:

1432850

Hom.:

Cov.:

AF XY:

0.0000253

AC XY:

AN XY:

710060

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000244

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000237

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.000478

Alfa

AF:

0.0000581

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 10, 2017	p.Arg980Cys (c.2938C>T) in exon 28 of the MYBPC3 gene (NM_000256.3; chr11-47355529-G-A) SCICD Classification: variant of uncertain significance based on weak case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: MYBPC3: Pathogenic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). However, there are several missense variants in MYBPC3 known to cause disease. MYBPC3 encodes cardiac myosin-binding protein C. It binds myosin heavy chain and titin. Phosphorylation of MYBPC3 modulates contraction of the sarcomere. Case data (not including our patient): 3 ClinVar: Laboratory for Molecular Medicine, Blueprint Genetics and Illumina classify this variant as a VUS Cases in the literature: 1 of 3600 patients in the Offspring cohort of the Framingham Heart study and the Jackson Heart Study (observational studies of cardiovascular disease) had this variant (Bick et al 2012; likely reundant with case submitted to ClinVar by LMM and Alfares et al 2015). This patient had a left ventricular wall thickness of 1.07cm and LVDD of 5.34cm, both within the normal range. 1 of 2912 patients with HCM/DCM tested at LMM (Alfares et al 2015; likely redundant with case submitted to ClinVar by LMM and Bick et al 2012) This variant co-occurred with an LP variant in TTN in one of the patients at our center. Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "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." Conservation data: The arginine at codon 980 is strongly conserved across species. Neighboring amino acids are also strongly conserved. Nearby pathogenic variants at this codon or neighboring codons: The only pathogenic variants at nearby codons +/- 10 amino acids are truncating variants. Population data: Highest MAF in European population: 0.004677%. The variant was reported online in 4 of 98,238 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 4 of 42,759 individuals of European descent (MAF=0.005%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2022	Reported in association with left ventricular dysfunction (Bick et al., 2012; Hazbroek et al., 2018), HCM (Walsh et al., 2017), and DCM (Verdonschot et al., 2020) in published literature; 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: 27532257, 29540472, 22958901, 32880476) -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 980 of the MYBPC3 protein (p.Arg980Cys). 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 individual(s) with abnormal left ventricular wall thickness, diameter, and/or function (PMID: 22958901, 27532257, 29540472, 32880476). ClinVar contains an entry for this variant (Variation ID: 42671). 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	Apr 16, 2024	This missense variant replaces arginine with cysteine at codon 980 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 33782553), in one individual affected with dilated cardiomyopathy (PMID: 32880476), in one individual affected with isolated left ventricular dysfunction (PMID: 22958901), and in one individual affected with unspecified heart disease (PMID: 29540472). This variant has been identified in 6/233074 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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 28, 2012

The Arg980Cys variant in MYBPC3 has not been previously reported in the literatu re nor previously been identified in >3600 individuals (>2200 Caucasian, >300 Bl ack) tested by our laboratory. Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity conclusively. Additional information is needed to fully as sess the clinical significance of the Arg980Cys variant. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 24, 2024

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 17, 2023

This missense variant replaces arginine with cysteine at codon 980 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 an individual affected with hypertrophic cardiomyopathy (PMID: 27532257), in an individual affected with dilated cardiomyopathy (PMID: 32880476), and in individuals affected with isolated left ventricular dysfunction and unspecified heart disease (PMID: 22958901, 29540472). This variant has been identified in 6/233074 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2020

The c.2938C>T (p.R980C) alteration is located in exon 28 (coding exon 28) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2938, causing the arginine (R) at amino acid position 980 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Paroxysmal atrial fibrillation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 08, 2015

- -

Left ventricular noncompaction 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

CardioboostCm

Benign

0.085

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

-0.022

MutationAssessor

Uncertain

2.7

M;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.2

D;.;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.71

MVP

0.88

MPC

0.97

ClinPred

0.95

GERP RS

5.0

Varity_R

0.43

gMVP

0.73

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.

rs397515994

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