rs397516000

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM5PP3_ModeratePP5

The NM_000256.3(MYBPC3):c.3065G>C(p.Arg1022Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,611,220 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. R1022S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:6

Conservation

PhyloP100: 7.56

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 Uncertain_significance. Variant got 5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47333683-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

PP5

Variant 11-47333682-C-G is Pathogenic according to our data. Variant chr11-47333682-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42682.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=1, Likely_pathogenic=4}. Variant chr11-47333682-C-G is described in Lovd as [Pathogenic]. Variant chr11-47333682-C-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.3065G>C	p.Arg1022Pro	missense_variant	29/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3065G>C	p.Arg1022Pro	missense_variant	29/35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3065G>C	p.Arg1022Pro	missense_variant	28/34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

GnomAD3 exomes

AF:

0.0000243

AC:

AN:

246674

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134018

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:

0.0000534

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000535

AC:

AN:

1458878

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

725852

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000666

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000481

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:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1022 of the MYBPC3 protein (p.Arg1022Pro). This variant is present in population databases (rs397516000, gnomAD 0.005%). This missense change has been observed in individuals with hypertrophic or dilated cardiomyopathy (PMID: 20433692, 22857948, 23396983, 24093860, 28771489, 30847666). ClinVar contains an entry for this variant (Variation ID: 42682). 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.Arg1022 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 22765922, 28790153), which suggests that this may be a clinically significant amino acid residue. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 16, 2019	The p.Arg1022Pro variant has been reported in >15 heterozygous individuals with HCM (Bos 2014, Brito 2005, Brito 2012, Cecconi 2016, Hazebroek 2015, Lopes 2013, Mademont-Soler 2017, Millat 2010, Walsh 2016, van Velzen 2018, Montserrat 2011- pers. comm., LMM data), 1 compound heterozygous individual with HCM (Rodriguez-Garcia 2010), and 1 compound heterozygous individual with DCM (Hazebroek 2015). This variant segregated with disease in 3 affected individuals and was absent in 2 family members with borderline LVH in one family (Rodriguez-Garcia 2010). This variant has been reported in ClinVar (Variation ID: 42682) and has been seen in 0.005% (6/127826) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP1, PP3. -
Uncertain significance, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with proline at codon 1022 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on the protein function. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 20624503, 20800588, 22857948, 23396983, 23782526, 24093860, 27532257, 28771489, 30847666, 31983221, 32841044, 32880476, 33495596, 33495597). This variant was observed together with pathogenic variants in different genes that could explain the observed phenotype (PMID: 20624503, 23782526; communication with an external laboratory). This variant has been reported in six affected individuals from two different families, but two possibly affected individuals did not carry this variant (PMID: 20433692). This variant has been identified in 7/278058 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 has been classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2023	This missense variant replaces arginine with proline at codon 1022 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on the protein function. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 20624503, 20800588, 22857948, 23396983, 23782526, 24093860, 27532257, 28771489, 30847666, 31983221, 32841044, 32880476, 33495596, 33495597). This variant was observed together with pathogenic variants in different genes that could explain the observed phenotype (PMID: 20624503, 23782526; communication with an external laboratory). This variant has been reported in six affected individuals from two different families, but two possibly affected individuals did not carry this variant (PMID: 20433692). This variant has been identified in 7/278058 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 has been classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 4

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Left ventricular noncompaction 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jul 25, 2019

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2024

The p.R1022P variant (also known as c.3065G>C), located in coding exon 29 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 3065. The arginine at codon 1022 is replaced by proline, an amino acid with dissimilar properties. This variant was reported in multiple individuals with features consistent with hypertrophic cardiomyopathy (HCM) (Brito D et al. Rev Port Cardiol, 2005 Sep;24:1137-46; Lopes LR et al. J Med Genet, 2013 Apr;50:228-39; Millat G et al. Eur J Med Genet, 2010 Jul;53:261-7; Rodríguez-García MI et al. BMC Med Genet, 2010 Apr;11:67; Marsiglia JD et al. Am Heart J, 2013 Oct;166:775-82; Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Sheikh N et al. Circulation, 2018 09;138:1184-1194; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2021

Identified in six individuals with HCM from two Spanish families, however, two relatives with suspected diagnoses of HCM did not harbor the R1022P variant (Rodriguez-Garcia et al., 2010); 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: 20624503, 27600940, 26383716, 22857948, 16335287, 20800588, 23396983, 24093860, 25351510, 27532257, 23782526, 24793961, 26743238, 20433692, 28771489, 29661763, 30847666, 32880476) -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Dec 02, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

CardioboostCm

Uncertain

0.16

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;T;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.9

M;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.9

D;.;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.014

D;D;D

Vest4

0.93

MVP

0.93

MPC

0.75

ClinPred

0.94

GERP RS

4.9

Varity_R

0.95

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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