rs377225516

Positions:

chr11-47351347-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000256.3(MYBPC3):c.184A>C(p.Thr62Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000234 in 1,601,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:6

Conservation

PhyloP100: 3.84

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17208287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.184A>C	p.Thr62Pro	missense_variant	2/35	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.184A>C	p.Thr62Pro	missense_variant	2/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.184A>C	p.Thr62Pro	missense_variant	2/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.184A>C	p.Thr62Pro	missense_variant, NMD_transcript_variant	2/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

228228

Hom.:

AF XY:

0.000137

AC XY:

AN XY:

123986

show subpopulations

Gnomad AFR exome

AF:

0.0000750

Gnomad AMR exome

AF:

0.0000306

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:

0.000263

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000236

AC:

342

AN:

1449466

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

167

AN XY:

719936

show subpopulations

Gnomad4 AFR exome

AF:

0.0000604

Gnomad4 AMR exome

AF:

0.00

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:

0.000295

Gnomad4 OTH exome

AF:

0.000234

GnomAD4 genome

AF:

0.000217

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000169

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:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2017	Variant summary: The MYBPC3 c.184A>C (p.Thr62Pro) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 14/54182 control chromosomes at a frequency of 0.0002584 in ExAC and at 0.00014 (36/255866 chrs tested) in gnomAD. These frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in several HCM patients without strong evidence supporting causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 05, 2014	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. p.Thr62Pro (c.184A>C, T62P) in the MYBPC3 gene. Given the weak case data (reviewed below) we consider this a variant of uncertain significance. The variant has been seen in two cases of HCM (not including this patient's family). There is no segregation data available. Millat et al (2010) observed the variant in one HCM proband from their French cohort of 192 unrelated HCM patients. The patient did not have any other rare variants in MYBPC3, MYH7, TNNT2, or TNNI3. Sam Baxter at LMM shared that they have seen this variant once before in a patient with HCM and classify it as a variant of uncertain significance. In silico analysis with PolyPhen-2 predicts the variant to be benign. Per communication from Sam Baxter at LMM their sarcomere-specific PolyPhen also predicts it to be benign. They report that benign predictions by this tool are accurate 89% of the time. This is a non-conservative substitution, changing a polar threonine to a non-polar proline (Grantham score is 38). The threonine at codon 62 is not well conserved across species (GERP score of 0.4; mouse, rat and frog have a lysine; chicken and zebrafish have an asparagine). I could find no other variants at this codon associated with disease and only one nearby variant associated with HCM (p.Thr59Ala (Niimura et al 2002)). In total the variant has been seen in 3 of 6682 published controls and individuals from publicly available population datasets. The variant was reported online in 3 of 4289 Caucasian individuals and 0 of 2193 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of March 25th, 2014). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was not observed in the following published control samples: 200 control individuals studied by Millat et al (2010). It is listed in dbSNP with submissions from NHLBI ESP and the LMM (rs377225516). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 25, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Thr62Pro vari ant in MYBPC3 has been reported in 1 individual with HCM (Millat 2010) and was i dentified by our laboratory in 1 Caucasian adult with HCM and 1 Caucasian indiv idual with teenage-onset DCM with LVH and conduction disease due to an alternate etiology. This variant has been identified in 34/116340 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSN P rs377225516). It was predicted to be benign using a computational tool clinica lly validated by our laboratory. This tool's benign prediction is estimated to b e correct 89% of the time (Jordan 2011). In summary, while the clinical signific ance of the p.Thr62Pro variant is uncertain, these data suggest that it is more likely to be benign. -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 62 of the MYBPC3 protein (p.Thr62Pro). This variant is present in population databases (rs377225516, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20624503). ClinVar contains an entry for this variant (Variation ID: 42577). 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 tolerated. 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	Jan 11, 2024	This missense variant replaces threonine with proline at codon 62 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 32841044). This variant has been identified in 39/259624 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. -

Cardiomyopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 02, 2023	This missense variant replaces threonine with proline at codon 62 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 32841044). This variant has been identified in 39/259624 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hypertrophic cardiomyopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 11, 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. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 30, 2024

The p.T62P variant (also known as c.184A>C), located in coding exon 2 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 184. The threonine at codon 62 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Millat G et al. Eur J Med Genet., 2010 Jul;53:261-7; Alfares AA et al. Genet Med, 2015 Nov;17:880-8). This alteration has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is poorly 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. -

Left ventricular noncompaction 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 11, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

CardioboostCm

Benign

0.0030

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.74

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.66

T;T;T

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.10

T;T;T

Polyphen

0.30

B;.;.

Vest4

0.73

MVP

0.82

MPC

0.37

ClinPred

0.061

GERP RS

0.40

Varity_R

0.77

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