11-47339715-C-T

Position:

chr11-47339715-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_000256.3(MYBPC3):c.2003G>A(p.Arg668His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,792 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R668P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 1 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:2

Conservation

PhyloP100: 7.39

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 Ig-like C2-type 5 (size 126) in uniprot entity MYPC3_HUMAN there are 34 pathogenic changes around while only 4 benign (89%) in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2003G>A	p.Arg668His	missense_variant	21/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2003G>A	p.Arg668His	missense_variant	21/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2003G>A	p.Arg668His	missense_variant	20/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.2003G>A		non_coding_transcript_exon_variant	21/27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000132

AC:

AN:

249084

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

135158

show subpopulations

Gnomad AFR exome

AF:

0.0000646

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:

0.000283

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461592

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000466

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000265

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 31, 2024	This missense variant replaces arginine with histidine at codon 668 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six unrelated individuals affected with hypertrophic cardiomyopathy as well as in eleven unaffected family members (PMID: 12818575, 15563892, 20359594, 25335496, 27000522). One of the affected individuals also carried a pathogenic truncation variant in the MYBPC3 gene that could explain the observed phenotype (PMID: 25335496). This variant occurs at an appreciable frequency in the general population and has been identified in 34/280486 chromosomes 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2022	ClinVar contains an entry for this variant (Variation ID: 164090). 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. This variant disrupts the p.Arg668 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 21302287), which suggests that this may be a clinically significant amino acid residue. 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 disruptive. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12818575, 15563892, 20359594, 25335496, 28790153). This variant is present in population databases (rs727503191, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 668 of the MYBPC3 protein (p.Arg668His). -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2018	The R668H variant of uncertain significance in the MYBPC3 gene has been reported previously in association with HCM (Morner et al., 2003; Song et al., 2005; Girolami et al., 2010). Initially, Morner et al., 2003 reported the R668H variant in two unrelated individuals with HCM, and was absent from 200 control alleles. Subsequently, this variant has been reported in at least one Chinese individual with HCM, and in one individual with HCM who also harbored additional variants in the MYH7 and MYBPC3 genes (Song et al., 2005; Girolami et al., 2010). Cann et al., 2016 reported this variant in one individual with HCM suspected on autopsy and in 27 relatives, three of which were reported to be clinically affected; detailed diagnostic criteria was not provided. This variant has also been reported in two unrelated individuals tested for cardiomyopathy at GeneDx. Additionally, the R668H variant was observed in 31/65808 alleles (~0.05%) from individuals of European (non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC).Although the R668H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 26, 2023	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 03, 2019	Variant classified as Uncertain Significance - Favor Benign. The p.Arg668His variant in MYBPC3 has been reported in at least 4 individuals with HCM (Morner 2003, Song 2005, Girolami 2010, Cann 2017); however, one of these individuals carried a second pathogenic variant in MYBPC3 that was sufficient to explain their disease (Girolami 2010, LMM data). The p.Arg668His variant has also been reported to segregate with cardiomyopathy in 2 families (Morner 2003, Cann 2017); however, detailed phenotypic information was not available. Furthermore, one clinically affected family member of a proband tested at our laboratory did not carry this variant (LMM data). The p.Arg668His variant has been identified in 0.026% (33/128360) of European chromosomes, including 1 homozygous individual, by gnomAD (http://gnomad.broadinstitute.org). This frequency is higher than expected for a pathogenic variant in the MYBPC3 gene. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain due to the presence of conflicting data, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, BS4, PP1, PP3. -
Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 12, 2015	- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 29, 2021

This missense variant replaces arginine with histidine at codon 668 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six unrelated individuals affected with hypertrophic cardiomyopathy as well as in eleven unaffected family members (PMID: 12818575, 15563892, 20359594, 25335496, 27000522). One of the affected individuals also carried a pathogenic truncation variant in the MYBPC3 gene that could explain the observed phenotype (PMID: 25335496). This variant occurs at an appreciable frequency in the general population and has been identified in 34/280486 chromosomes 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2024

The p.R668H variant (also known as c.2003G>A), located in coding exon 21 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2003. The arginine at codon 668 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in individuals reported to have hypertrophic cardiomyopathy (HCM) (Mörner S et al. J Mol Cell Cardiol. 2003;35:841-9; Song L et al. Clin Chim Acta. 2005;351:209-16; Wang H et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2008;36:1059-62; Girolami F et al. J Am Coll Cardiol. 2010;55:1444-53), and also in a sudden cardiac death case (Cann F et al. Clin Genet. 2016 Mar). Family studies have identified this variant in some reportedly affected members, but also multiple unaffected family members, and this alteration has been reported to co-occur with alterations in other cardiac-related genes in one family (Mörner S et al. J Mol Cell Cardiol. 2003;35:841-9; Wang H et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2008;36:1059-62; Girolami F et al. J Am Coll Cardiol. 2010;55:1444-53; Cann F et al. Clin Genet. 2016 Mar). 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 data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jul 21, 2015

This MYBPC3 Arg668His has been previously identified in multiple unrelated HCM cases (Morner S. et al., 2003; Song L. et al., 2005; Alfares AA. et al., 2015). Familial segregation in one HCM family by Wang H. et al., (2008) found 3 HCM affecteds and 1 clinically unaffected to carry this variant. Similarly, familial investigation by Morner S. et al., (2003) identified clinically unaffected individuals to carry this MYBPC3 Arg668His variant. We have identified the MYBPC3 Arg668His variant in an HCM proband where two additional variants in MYBPC3 and MYH7 have also been observed in the family (Girolami F, et al., 2010). One of the additional variants (MYBPC3 Gln969*) is well described as disease-causing. Segregation analysis showed this MYBPC3 Arg668His variant to be present in one other clinically unaffected family member who carried an additional MYH7 Arg1079Gln variant (VUS). This variant is not observed in the 1000 genomes project (http://www.1000genomes.org/), but occurs in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.0002696. Furthermore, the MYBPC3 Arg668His has been identified in isolation in a heart study population (Bick AG, et al., 2012) and an HCM cohort (Alfares AA et al., 2015), but there is no further evidence provided in these studies to support a pathogenic role. Arginine (Arg) at position 668 is highly conserved across distantly related species and in silico tools SIFT and MutationTaster predict the impact of this variant to be "deleterious" and "disease-causing", respectively. No prediction is made by PolyPhen-HCM. Due to the possibility of incomplete disease penetrance in our family, limited segregation analysis due to small number of informative individuals, and co-occurrence with a MYBPC3 variant (Gln969*) that explains the disease phenotype, we classify this MYBPC3 Arg668His variant as one of "uncertain significance". -

Hypertrophic cardiomyopathy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

CardioboostCm

Uncertain

0.12

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.1

M;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.5

D;.;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Vest4

0.85

MVP

0.91

MPC

0.92

ClinPred

0.62

GERP RS

4.9

Varity_R

0.45

gMVP

0.72

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

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