11-47337391-C-T

Position:

chr11-47337391-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_000256.3(MYBPC3):c.2602G>A(p.Gly868Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,580,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G868D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 7.57

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_pathogenic. Variant got 6 ACMG points.

PM1

In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 50 pathogenic changes around while only 6 benign (89%) in NM_000256.3

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2602G>A	p.Gly868Ser	missense_variant, splice_region_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2602G>A	p.Gly868Ser	missense_variant, splice_region_variant	25/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2602G>A	p.Gly868Ser	missense_variant, splice_region_variant	24/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.*107G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	25/27	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151972

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:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000614

AC:

AN:

227862

Hom.:

AF XY:

0.0000647

AC XY:

AN XY:

123568

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000595

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000287

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000388

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000476

AC:

AN:

1428416

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

706116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000457

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000311

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151972

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74232

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:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 29, 2023	This missense variant replaces glycine with serine at codon 868 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). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 25 of the MYBPC3 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. An experimental mini-gene splicing assay has shown that this variant may cause partially aberrant splicing (PMID: 28679633); the clinical relevance of this observation is not known. This variant has been reported in an individual affected with dilated cardiomyopathy who also carried a pathogenic truncation variant in the TTN gene that could explain the observed phenotype (PMID: 32826072). This variant has also been reported in an individual affected with Wolff-Parkinson-White syndrome, supraventricular tachycardia, and Ebstein anomaly (PMID: 32233023) and in an individual affected with left ventricular noncompaction (PMID: 30471092). This variant has been identified in 14/227862 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 05, 2019	- -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 868 of the MYBPC3 protein (p.Gly868Ser). This variant also falls at the last nucleotide of exon 25, which is part of the consensus splice site for this exon. This variant is present in population databases (rs775890771, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of left ventricular noncompaction (PMID: 34088380). ClinVar contains an entry for this variant (Variation ID: 518630). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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	Sep 17, 2023	This missense variant replaces glycine with serine at codon 868 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). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 25 of the MYBPC3 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. An experimental mini-gene splicing assay has shown that this variant may cause partially aberrant splicing (PMID: 28679633); the clinical relevance of this observation is not known. This variant has been reported in an individual affected with dilated cardiomyopathy who also carried a pathogenic truncation variant in the TTN gene that could explain the observed phenotype (PMID: 32826072). This variant has also been reported in an individual affected with Wolff-Parkinson-White syndrome, supraventricular tachycardia, and Ebstein anomaly (PMID: 32233023) and in an individual affected with left ventricular noncompaction (PMID: 30471092). This variant has been identified in 14/227862 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

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

Jan 20, 2020

Variant summary: MYBPC3 c.2602G>A (p.Gly868Ser) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.1e-05 in 227862 control chromosomes (gnomAD, exomes only). This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (6.1e-05 vs 0.001), allowing no conclusion about variant significance. c.2602G>A has been reported in the literature in a healthy individual (Kapplinger_2014). This report does 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. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. 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

Apr 11, 2022

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2022

The p.G868S variant (also known as c.2602G>A), located in coding exon 25 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2602.This alteration changes the glycine at codon 868 to serine, an amino acid with similar properties. This alteration was observed in a reportedly healthy control cohort in a study of hypertrophic cardiomyopathy genetic testing, and has also been detected in a left ventricular non-compaction cardiomyopathy cohort and a Wolff-Parkinson-White cohort; however details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Richard P et al. Clin. Genet., 2019 Mar;95:356-367; Coban-Akdemir ZH et al. Am J Med Genet A, 2020 06;182:1387-1399). In a minigene assay, this alteration resulted in some aberrant splicing, as did the reference to a lesser degree; however, the physiologic relevance of these data are unclear (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. The amino acid position is not well conserved in available vertebrate species, and the missense change is predicted to be tolerated 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

0.19

CardioboostCm

Benign

0.014

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;T

Eigen

Benign

0.0052

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.46

N;.;N

REVEL

Benign

0.12

Sift

Uncertain

0.0050

D;.;D

Sift4G

Uncertain

0.014

D;D;D

Vest4

0.30

MVP

0.84

MPC

0.42

ClinPred

0.22

GERP RS

4.5

Varity_R

0.18

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.18

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