11-47335996-G-T

Position:

chr11-47335996-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong

The NM_000256.3(MYBPC3):c.2618C>A(p.Pro873His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,528,202 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P873L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:14

Conservation

PhyloP100: 9.58

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 8 ACMG points.

PM1

In a domain Fibronectin type-III 2 (size 95) in uniprot entity MYPC3_HUMAN there are 23 pathogenic changes around while only 7 benign (77%) in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47335996-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2618C>A	p.Pro873His	missense_variant	26/35	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.2618C>A	p.Pro873His	missense_variant	26/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2618C>A	p.Pro873His	missense_variant	25/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.*123C>A		non_coding_transcript_exon_variant	26/27	5		ENSP00000444259.1	F5GZR4
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.*123C>A		3_prime_UTR_variant	26/27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152136

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000794

AC:

AN:

176378

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

95100

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:

0.0000564

Gnomad NFE exome

AF:

0.000157

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000618

AC:

AN:

1376066

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

676476

show subpopulations

Gnomad4 AFR exome

AF:

0.0000329

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:

0.0000758

Gnomad4 OTH exome

AF:

0.0000529

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74316

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:

0.0000588

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2023	Variant summary: MYBPC3 c.2618C>A (p.Pro873His) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 176378 control chromosomes, predominantly at a frequency of 0.00016 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2618C>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy and unspecified individuals from large public datasets, without strong evidence for causality (examples, Nanni_2003, Andreasen_2013, Amendola_2015, Stava_2022, vanSpaendonck_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 23299917, 35653365, 23349452, 12951062). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 05, 2018	The p.Pro873His variant in MYBPC3 has been reported in the heterozygous state in 2 individuals with HCM and 2 individuals with DCM (Ingles 2005, Maron 2012, van Spaendonck-Zwarts 2013, LMM data). It segregated with DCM or HCM in 4 affected individuals from 1 family (LMM data). It has also been identified in the homozyg ous state in an individual with HCM with no reported family history of disease ( Nanni 2003) and in an additional individual with severe HCM whose brother was al so homozygous for the variant and had mild symptoms (Kissopoulou 2018). Several reportedly unaffected family members (ages 10-54) were heterozygous for the vari ant (Kissopoulou 2018). This variant has also been reported by other clinical la boratories in ClinVar (Variation ID: 30143) and has also been identified in 0.01 % (14/98008) European chromosomes, including 1 homozygote, by gnomAD (http://gno mad.broadinstitute.org/). Computational prediction tools and conservation analys is suggest that the p.Pro873His variant may impact the protein. In summary, due to conflicting evidence, the clinical significance of the p.Pro873His variant is uncertain. ACMG/AMP Criteria applied: PP1, PP3, PS4_Supporting, BS1_Supporting. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 08, 2015	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 -

Hypertrophic cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces proline with histidine at codon 873 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental study has indicated that this missense may impact protein folding (PMID: 26688216), but the clinical relevance of this observation is not known. This variant has been reported in the heterozygous state in individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 21839045; Kassem 2017) and with dilated cardiomyopathy (PMID: 23349452). This variant has been reported in homozygosity in an individual affected with hypertrophic cardiomyopathy (PMID: 12951062), as well as in two related individuals from a Swedish family affected with hypertrophic cardiomyopathy (PMID: 29663722). In this Swedish family, seven unaffected heterozygous carriers were reported. This variant has also been identified in 15/207756 chromosomes (14/98008 Non-Finnish European chromosomes, including one homozygous individual) in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with uncertain functional impact that has been reported in affected individuals as well as in the general population. In a family study, multiple unaffected heterozygotes were observed in addition to two affected homozygotes. Available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Feb 20, 2020	The MYBPC3 Pro873His variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.00014 which is higher then expected for HCM. We have identified the MYBPC3 Pro873His variant in an HCM proband where one additional MYBPC3 (Asp745Gly) variant of uncertain significance has also been observed (Ingles J., et al 2005). In this proband we recently identified a third variant in CSRP3 (Arg146Cys). Both MYBPC3 variants were found to segregate to an affected first degree family member. In addition, this variant has been identified in one HCM individual who was homozygous for the variant (Nanni L., et al 2003) and has also been identified in one DCM patient (Spaendonck-Zwarts K., et al 2013). Predictions from in silico tools (SIFT, PolyPhen-2, MutationTaster) are supportive of a deleterious effect. However, due to co-occurrence in our proband with an additional MYBPC3 variant, limited familial data, and insufficient evidence, we classify this MYBPC3 Pro873His variant as one of "uncertain significance". -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 873 of the MYBPC3 protein (p.Pro873His). This variant is present in population databases (rs371401403, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12951062, 29663722, 36252119; Invitae). ClinVar contains an entry for this variant (Variation ID: 30143). 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: 26688216). 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. -

Hypertrophic cardiomyopathy 4

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2005	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (13 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (13 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Fibronectin type III domain (DECIPHER). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. The p.(Pro873Leu) variant has been reported multiple times as VUS in ClinVar and has been reported in individuals with HCM, DCM and LVNC (PMIDs: 33495597, 21551322, 27173948, 27600940). The p.(Pro873Gln) variant has been reported in one individual with HCM (PMID: 22267749). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in homozygous and compound heterozygous state in association with HCM (PMID: 12951062, 16199542, 25335496, 29663722) and in a heterozygous individual with DCM (PMID: 23349452). It has also been reported multiple times as VUS in ClinVar. (I) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate in one family with HCM, whereby individuals homozygous for the variant are affected and individuals heterozygous for the variant are unaffected (PMID: 29663722). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 28, 2023	This missense variant replaces proline with histidine at codon 873 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). An experimental functional study has indicated that this variant may impact protein folding (PMID: 26688216), but the clinical relevance of this observation is not known. This variant has been reported in the heterozygous state in individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 21839045, 33495597; DOI:10.1016/j.ejmhg.2017.05.002) and in an individual affected with dilated cardiomyopathy (PMID: 23349452). This variant has also been reported in homozygosity in an individual affected with hypertrophic cardiomyopathy (PMID: 12951062), as well as in two related individuals from a family affected with hypertrophic cardiomyopathy (PMID: 29663722). In this family, seven unaffected heterozygous carriers were reported. This variant has been identified in 15/207756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with uncertain functional impact that has been reported in affected individuals as well as in the general population. 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	Jun 07, 2023	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2024	Reported in the heterozygous state in individuals with confirmed cardiomyopathy or referred for cardiomyopathy genetic testing at GeneDx and in the published literature; however, multiple individuals were found to harbor additional cardiogenetic variants (PMID: 33495597, 37431535, 25351510, 36252119, 16199542); Observed in the homozygous state in an individual with moderate/severe hypertrophy, left ventricular outflow tract obstruction, and non-sustained ventricular tachycardia (PMID: 12951062); 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: 21415409, 22515980, 15115610, 25637381, 17655857, 23349452, 23299917, 21839045, 25335496, 26688216, 21551322, 18761664, 20031583, 28518168, 28679633, 16199542, 12951062, 37937776, 36252119, 33495597, 37652022, 25351510, 35653365, 37431535, 29663722) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 26, 2020	The MYBPC3 c.2618C>A; p.Pro873His variant (rs371401403) is reported in the literature in several homozygous individuals affected with hypertrophic cardiomyopathy (HCM), as well as unaffected heterozygous relatives (Kassem 2017, Kissopoulou 2018, Nanni 2003). In addition, this variant has been reported in a proband with dilated cardiomyopathy (van Spaendonck-Zwarts 2013), and in several other individuals with HCM that carried a second missense variant of uncertain clinical significance (Maron 2012). The p.Pro873His variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (14/98008 alleles, including one homozygote) in the Genome Aggregation Database. The proline at codon 873 is highly conserved, and computational analyses (REVEL) predict that this variant is deleterious. Indeed, structural studies suggest the p.Pro873His variant leads to misfolding of the C7 domain (Nadvi 2016), although the clinical impact of this misfolding is not clear. Further, another amino acid substitution at this codon (p.Pro873Leu) has been reported in an individual with HCM, though it was not determined whether variant is disease-causing (Probst 2011). Due to limited and conflicting information, including an unclear pattern of inheritance, the clinical significance of the p.Pro873His variant is uncertain at this time. References: Kassem HS et al. A comparative study of mutation screening of sarcomeric genes (MYBPC3, MYH7, TNNT2) using single gene approach versus targeted gene panel next generation sequencing in a cohort of HCM patients in Egypt. Egypt J Med Hum Genet. 2017 Oct;18(4):381-387. Kissopoulou A et al. Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy. ESC Heart Fail. 2018 Aug;5(4):716-723. Maron BJ et al. Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors. Heart Rhythm. 2012 Jan;9(1):57-63. Nadvi NA et al. Clinically Linked Mutations in the Central Domains of Cardiac Myosin-Binding Protein C with Distinct Phenotypes Show Differential Structural Effects. Structure. 2016 Jan 5;24(1):105-115. Nanni L et al. Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. Biochem Biophys Res Commun. 2003 Sep 19;309(2):391-8. Probst S et al. Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. Circ Cardiovasc Genet. 2011 Aug 1;4(4):367-74. van Spaendonck-Zwarts KY et al. Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience. Eur J Heart Fail. 2013 Jun;15(6):628-36. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 09, 2021

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2021

The c.2618C>A (p.P873H) alteration is located in exon 26 (coding exon 26) of the MYBPC3 gene. This alteration results from a C to A substitution at nucleotide position 2618, causing the proline (P) at amino acid position 873 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;T;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

4.6

H;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-8.2

D;.;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.92

MVP

0.96

MPC

0.89

ClinPred

0.99

GERP RS

5.3

Varity_R

0.96

gMVP

0.85

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