11-47341207-C-G

Position:

chr11-47341207-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5

The NM_000256.3(MYBPC3):c.1828G>C(p.Asp610His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,598,984 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. D610N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9

Conservation

PhyloP100: 7.48

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 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47341207-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42575.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=7}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant 11-47341207-C-G is Pathogenic according to our data. Variant chr11-47341207-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42576.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=9}. Variant chr11-47341207-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.1828G>C	p.Asp610His	missense_variant	19/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.1828G>C	p.Asp610His	missense_variant	19/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.1828G>C	p.Asp610His	missense_variant	18/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.1828G>C	p.Asp610His	missense_variant, NMD_transcript_variant	19/27	5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152146

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:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000315

AC:

AN:

222558

Hom.:

AF XY:

0.0000249

AC XY:

AN XY:

120384

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:

0.0000508

Gnomad NFE exome

AF:

0.0000601

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1446838

Hom.:

Cov.:

AF XY:

0.0000640

AC XY:

AN XY:

718236

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:

0.0000764

Gnomad4 NFE exome

AF:

0.0000805

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74310

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:

0.000377

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Left ventricular noncompaction 10

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 05, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID#42576; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20624503, 20800588, 22361390, 27532257, 28074886, 28538763, 22958901, 27618852, 27535533, 28356264, 18533079, 21835320, 26582918, 29032884, 33782553, 32746448) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 05, 2022	- -

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces aspartic acid with histidine at codon 610 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 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20624503, 28356264, 28538763, 32531501, 33782553, 33495597). One of these individuals was compound heterozygous with a known pathogenic mutation in the same gene (PMID: 28538763). While this individual was reported to show severe phenotype, all other carriers of either of the two variants showed no clinical signs of hypertrophic cardiomyopathy. This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221) and in two individuals affected with sudden infant death syndrome (PMID: 22361390, 28074886). This variant has been identified in 8/253926 chromosomes in the general population 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 610 of the MYBPC3 protein (p.Asp610His). This variant is present in population databases (rs371564200, gnomAD 0.008%). This missense change has been observed in individuals with hypertrophic cardiomyopathy, sudden infant death syndrome, and/or ventricular fibrillation (PMID: 8533079, 20624503, 22361390, 25740977, 28074886, 28356264, 29032884). ClinVar contains an entry for this variant (Variation ID: 42576). 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.Asp610 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22857948, 33782553, 34097875; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 20, 2022	This missense variant replaces aspartic acid with histidine at codon 610 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 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20624503, 28356264, 28538763, 32531501, 33782553, 33495597). One of these individuals was compound heterozygous with a known pathogenic mutation in the same gene (PMID: 28538763). While this individual was reported to show severe phenotype, all other carriers of either of the two variants showed no clinical signs of hypertrophic cardiomyopathy. This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221) and in two individuals affected with sudden infant death syndrome (PMID: 22361390, 28074886). This variant has been identified in 8/253926 chromosomes in the general population 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 07, 2018

The p.Asp610His variant in MYBPC3 has been detected in 8 individuals with HCM (O livotto 2008, Millat 2010, Brito 2012, Rafael 2017 and LMM unpublished data) and one child who died from sudden infant death syndrome (SIDS; Brion 2012). Two of these individuals carried additional pathogenic variants and one individual was homozygous for the p.Asp610His variant (Rafael 2017, LMM data). In one family, this variant segregated with disease in 2 affected relatives, but was not presen t in an additional affected relative, raising the possibility that it may not be disease causing. The variant has also been identified in multiple older individ uals without disease. This variant has also been reported in ClinVar (Variation ID: 42576). This variant has also been identified in 6/113666 European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs371564200). Computational prediction tools suggest that the p.Asp610His variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, the clinical significance of the p.Asp 610His variant is uncertain. ACMG/AMP Criteria applied: PP3; PS4_Supporting; BP2 . -

Hypertrophic cardiomyopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 26, 2016

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The p.D610H variant (also known as c.1828G>C), located in coding exon 19 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 1828. The aspartic acid at codon 610 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM), but several of the probands were also heterozygous for pathogenic variants in other HCM-associated genes (Millat G et al. Eur J Med Genet 2010 Sep-Oct;53:261-7; Olivotto I et al. J. Am. Coll. Cardiol., 2011 Aug;58:839-48; Calore C et al. J. Med. Genet., 2015 May;52:338-47; Galati G et al. Circ Heart Fail, 2016 Sep;9; Rafael JF et al. Arq. Bras. Cardiol., 2017 Apr;108:354-360; Maurizi N et al. JAMA Cardiol, 2018 Jun;3:520-525). This alteration was also reported in cases of sudden infant death syndrome; however, limited clinical information was provided (Brion M et al. Forensic Sci. Int., 2012 Jun;219:278-81; Neubauer J et al. Eur. J. Hum. Genet., 2017 04;25:404-409). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Uncertain

0.17

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;T;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.6

H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.2

D;.;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.95

MVP

0.94

MPC

0.90

ClinPred

0.97

GERP RS

4.6

Varity_R

0.77

gMVP

0.97

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