rs397516070

Positions:

chr11-47348486-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000256.3(MYBPC3):c.710A>C(p.Tyr237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,266 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y237C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 7.97

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a domain Ig-like C2-type 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47348486-T-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 11-47348486-T-G is Pathogenic according to our data. Variant chr11-47348486-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 42787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47348486-T-G is described in Lovd as [Likely_benign]. Variant chr11-47348486-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.710A>C	p.Tyr237Ser	missense_variant	6/35	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.710A>C	p.Tyr237Ser	missense_variant	6/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.710A>C	p.Tyr237Ser	missense_variant	6/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.710A>C	p.Tyr237Ser	missense_variant, NMD_transcript_variant	6/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461266

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2018	The p.Tyr237Ser variant in MYBPC3 has been identified in at least 10 individuals with HCM and segregated with disease in 10 affected relatives, including 2 obli gate carriers, from 2 families (Morner 2003, Walsh 2017, GeneDx pers comm., LMM data). It has not been identified in large population studies. Computational pre diction tools and protein structural modeling suggest that the p.Tyr237Ser varia nt impacts the protein (Govada 2008). Additionally, other variants at this posit ion (p.Tyr237His and p.Tyr237Cys) have been reported in individuals with HCM, su ggesting that variation at this position is not tolerated (Waldmuller 2008, Garc ia-Castro 2009). In summary, the p.Tyr237Ser variant meets criteria to be classi fied as pathogenic for HCM in an autosomal dominant manner based on case observa tions, segregation studies, and absence from controls. ACMG/AMP criteria applied : PP1_VeryStrong, PM2, PS4_Moderate, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 237 of the MYBPC3 protein (p.Tyr237Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12818575, 24111713, 27532257). ClinVar contains an entry for this variant (Variation ID: 42787). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 30611859). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces tyrosine with serine at codon 237 in the Ig-like domain C1 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using a transgenic knock-in mouse model has shown that this variant causes normal protein expression, but with evidence of alteration in C1 domain interactions (PMID: 30611859). This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12818575, 24111713, 25351510, 25611685, 27532257, 28971120, 30297972, 32841044, 33495596, 33495597, 33673806, 37477868). It has been shown that this variant segregates with disease in multiple affected individuals across two families (ClinVar SCV000059314.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2024	Observed in multiple unrelated patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 24111713, 12818575, 27532257); 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: 15115610, 23527136, 12818575, 28679633, 27532257, 24111713, 30611859, 19150014, 18258667, 35653365, 33673806, 34542152) -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 23, 2021

- -

Hypertrophic cardiomyopathy 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Region Ostergotland

Jun 17, 2020

PS4, PM1, PM2, PP3, PM5, PP1 -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 15, 2015

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

The p.Y237S pathogenic mutation (also known as c.710A>C), located in coding exon 6 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 710. The tyrosine at codon 237 is replaced by serine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in several families (Mörner S et al. J. Mol. Cell. Cardiol., 2003 Jul;35:841-9; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203; external communication; Ambry internal data). Functional studies performed in skinned myofibrils from an MYBPC3 knockout mouse virally transfected with Y237S suggest that this alteration accelerates contractile function; however, the clinical relevance of those results is unclear (Doh CY et al. Biochim Biophys Acta Mol Basis Dis, 2019 Mar;1865:661-677). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 12, 2012

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.Tyr237Ser (c.710A>C) in MYBPC3. Based on the data reviewed below, we consider this variant to be a variant of uncertain significance, probably disease causing. This variant has been reported in one familial HCM case in Northern Sweden. The proband with this variant was diagnosed with HCM at 37. He had 11 first degree relatives, seven of whom were evaluated. Out of the seven, one relative also had HCM. Co-segregation analysis was not performed (Morner et al., 2003). This is a conservative amino acid change with a neutral polar Tyrosine replaced with a neutral polar Serine. Tyrosine at position 237 is highly conserved in MYBPC3 across species. In silico analysis (PolyPhen 2) predicts the variant to be probably damaging. Other variants at this same codon have been reported in association with HCM: p.Tyr237His (Waldmuller et al., 2008); p.Tyr237Cys (Garcia-Castro et al., 2009); p.Tyr237X (Ehlermann et al., 2008), as have variants at nearby codons: p. Asp228Asn (Andersen et al., 2001; Andersen et al., 2004); p.Ser236Gly (Daehmlow et al., 2002; Fokstuen et al., 2008; Girolami et al., 2006; Jaaskerlainen et al., 2002; Morita et al., 2006, and Wang et al., 2009) and p.Glu240Asp (Girolami et al., 2006). In total, the variant has not been observed in ~7,000 control individuals from published studies and publicly available general population samples. The variant has not been seen in Familion's control population of 400 presumably health individuals. Morner et al (2003) reported the absence of the variant in at least 100 presumably healthy control individuals. The variant is not reported in dbSNP or 1000 genomes (as of January 29, 2014) The variant is not listed in NHLBI Exome Sequencing Project (as of January 29, 2014), which includes variant calls on ~6,500 Caucasian and African American individuals. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.6

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-7.8

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.95

MutPred

0.97

Gain of disorder (P = 0.0039);Gain of disorder (P = 0.0039);Gain of disorder (P = 0.0039);

MVP

0.97

MPC

0.98

ClinPred

1.0

GERP RS

5.1

Varity_R

0.88

gMVP

0.88

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