rs397516068

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_000256.3(MYBPC3):c.655G>T(p.Val219Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V219L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 29)

Consequence

MYBPC3
NM_000256.3 missense, splice_region

Scores

Splicing: ADA: 0.9972

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.08

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a strand (size 7) in uniprot entity MYPC3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000256.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47348541-C-G is described in Lovd as [Pathogenic].

PP3

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

PP5

Variant 11-47348541-C-A is Pathogenic according to our data. Variant chr11-47348541-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47348541-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.655G>T	p.Val219Phe	missense_variant, splice_region_variant	Exon 6 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.655G>T	p.Val219Phe	missense_variant, splice_region_variant	Exon 6 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.655G>T	p.Val219Phe	missense_variant, splice_region_variant	Exon 6 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.655G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152112

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243260

Hom.:

AF XY:

0.00000757

AC XY:

AN XY:

132108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74452

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:

0.0000147

Gnomad4 OTH

AF:

0.000473

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 219 of the MYBPC3 protein (p.Val219Phe). 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 hypertrophic cardiomyopathy (PMID: 20624503, 26914223, 35838873; internal data). ClinVar contains an entry for this variant (Variation ID: 188531). 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. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (Crehalet et al. 2012. Cardiogenetics; http://dx.doi.org/10.4081/cardiogenetics.2012.e6). This variant disrupts the c.655G nucleotide in the MYBPC3 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15519027, 20031602, 20031618, 20624503, 26914223). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Nov 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Val219Phe variant in MYBPC3 has been reported in two adults with HCM (Millat 2010, Crehalet 2012) and was absent in large population studies. This variant is located in the first base of the exon, which is part of the 3’ splice region. In vitro studies showed that this variant results in skipping of exon 6 (Crehalet 2012), which is predicted to cause a frameshift and a premature termination codon, leading to a truncated or absent protein. Heterozygous loss-of-function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -

not provided

Pathogenic:1

Jul 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In vitro studies have shown that c.655 G>T results in the skipping of exon 6, which is expected to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation (Crehalet et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); 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: 7446532, 28265379, 27535533, 28679633, 26914223, 20624503, 31589614, 34097875, Crehalet_2012_Cardiogenetics) -

Cardiovascular phenotype

Pathogenic:1

May 16, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.655G>T variant (also known as p.V219F) is located in coding exon 6 of the MYBPC3 gene. The valine at codon 219 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 6. This variant has been reported in several hypertrophic cardiomyopathy (HCM) cohorts (Millat G et al. Eur J Med Genet. 2010;53:261-7; Crehalet H et al. Cardiogenetics. 2012;2:e6; Murphy SL et al. J Cardiovasc Transl Res. 2016;9:153-61). In addition, this alteration causes complete skipping of exon 6 in an in vitro minigene assay (Crehalet H et al. Cardiogenetics. 2012;2:e6). Skipping of exon 6 is expected to lead to a frameshift with a predicted alternative stop (p.V219Rfs*42). A disease-causing mutation in the same nucleotide, c.655G>C, is also reported to lead to skipping of exon 6 (Van Driest SL et al. J. Am. Coll. Cardiol. 2004;44:1903-10; Crehalet H et al. Cardiogenetics. 2012;2:e6; Walsh R et al. Genet. Med. 2017;19:192-203). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

CardioboostCm

Uncertain

0.73

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;T;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.76

MutPred

0.57

Gain of ubiquitination at K218 (P = 0.1278);Gain of ubiquitination at K218 (P = 0.1278);Gain of ubiquitination at K218 (P = 0.1278);

MVP

0.93

MPC

0.94

ClinPred

0.95

GERP RS

2.9

Varity_R

0.67

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.86

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