rs727503188

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3PP5

The NM_000256.3(MYBPC3):c.2449C>T(p.Arg817Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R817G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 4.91

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 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47337544-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

PP5

Variant 11-47337544-G-A is Pathogenic according to our data. Variant chr11-47337544-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164078.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2449C>T	p.Arg817Trp	missense_variant	25/35	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.2449C>T	p.Arg817Trp	missense_variant	25/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2449C>T	p.Arg817Trp	missense_variant	24/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.2414-33C>T		intron_variant, NMD_transcript_variant		5		ENSP00000444259

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249226

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135206

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 21, 2022	The MYBPC3 c.2449C>T variant is classified as VUS (PS4_Moderate, PM2, PP3) The MYBPC3 c.2449C>T variant is a single nucleotide change in exon 25/35 of the MYBPC3 gene, which is predicted to change the amino acid arginine at position 817 in the protein, to tryptophan. The variant has been reported in at least 6 probands with a clinical presentation of Hypertrophic cardiomyopathy (PS4_Moderate) (PMID#25351510, 28749478, 33782553). Other variants at this same amino acid have also been reported in individuals with HCM (p.Arg817Gln/Gly) (PMID#26914223, 3378553). This variant is absent from population databases (PM2), is reported in dbSNP (rs727503188), is reported as ?disease causing in HGMD (CM1516385) and is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar#164078). Computational predictions support a deleterious effect on the gene or gene product (PP3). This variant has also been reported in a homozygous state in a foetus with hydrops fatalis. Parental testing was implied and indicated a 'lack of phenotype in carrier' however this was not confirmed with cardiac imaging (PubMed#28749478). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Oct 13, 2024	This variant (GRCh38; NM_000256.3:c.2449C>T:p.Arg817Trp) results in a missense mutation with the conversion of Arginine (Basic amino acid) to Tryptophane (Nonpolar amino acid) in the MYBPC3 protein. Located in a mutational hot spot and/or critical and well established functional domain without benign variation. Not observed at significant frequency in large population cohorts (gnomAD). Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. This variant has a strong Conservation score. Multiple lines of computational evidence of this variant support a deleterious effect on the gene or gene product for this variant. ClinVar contains an entry for this variant (Variation ID:164078). This variant is associated with the following publications: PubMed: 25351510, 28749478, 36264615, 33782553, 26914223 In summary, this variant meets our criteria for classification as Likely pathogenic based on the evidence outlined. -

Left ventricular noncompaction 10

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 05, 2024

- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 817 of the MYBPC3 protein (p.Arg817Trp). 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 nonimmune hydrops fetalis and hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 28749478, 33782553, 36264615; Invitae). ClinVar contains an entry for this variant (Variation ID: 164078). 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. This variant disrupts the p.Arg817 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26914223, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 12, 2013

proposed classification - variant undergoing re-assessment, contact laboratory -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2024

Identified in association with HCM in published literature (PMID: 27532257, 25351510, 33782553); Reported to be homozygous in at least one fetus with nonimmune hydrops fatalis (PMID: 28749478); Identified in a patient with HCM and status-post heart transplant who also harbored a second pathogenic variant in the MYBPC3 gene (PMID: 36136372); 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: 25351510, 26914223, 28679633, 34428338, 33782553, 27532257, 34645488, 34515413, 28749478, 36136372) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

CardioboostCm

Uncertain

0.70

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

D;T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

-0.037

MutationAssessor

Pathogenic

4.0

H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.2

D;.;D

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.81

MVP

0.91

MPC

0.85

ClinPred

0.99

GERP RS

3.7

Varity_R

0.79

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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