rs397515885

Positions:

chr11-47351427-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4_Moderate

The NM_000256.3(MYBPC3):c.104G>A(p.Arg35Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000658 in 1,609,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R35W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 4.59

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 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47351428-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.12822846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.104G>A	p.Arg35Gln	missense_variant	2/35	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.104G>A	p.Arg35Gln	missense_variant	2/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.104G>A	p.Arg35Gln	missense_variant	2/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.104G>A		non_coding_transcript_exon_variant	2/27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000664

AC:

AN:

241052

Hom.:

AF XY:

0.0000760

AC XY:

AN XY:

131504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000680

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000672

AC:

AN:

1457444

Hom.:

Cov.:

AF XY:

0.0000635

AC XY:

AN XY:

724866

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000900

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000228

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000661

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Arg35Gln variant in MYBPC3 has been reported in 4 individuals with hypertrophic cardiomyopathy, and at least 1 individual with HCM who was double heterozygous for a different likely pathogenic variant in MYBPC3 (Berge 2014 PMID: 24111713, Thompson 2021 PMID: 33782553, LMM data). It has also been identified in 0.07% (12/17642) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 42503). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP2. -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 11, 2016	p.Arg35Gln (c.104G>A) in exon 2 of the MYBPC3 gene (NM_000256.3) We have seen this variant in a person with HCM who had another very likely pathogenic variant. Testing was done through Invitae. Given the relatively high frequency in an ethnicity-matched population dataset and the presence of another likely pathogenic variant, we consider this variant of uncertain signficance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 3 unrelated cases of HCM (not including this patient's family). This is moderate case data. Berge et al., 2013 reported the variant in 2 HCM probands in Norway. LMM has seen it in a Caucasian person with HCM. The Invitae report notes that "The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine...algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0")." The variant was reported online in 7 of 44,255 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 10/11/2016). Specifically, the variant was observed in 6 of 3237 East Asian people (AF: 0.09%) and 1 of 24,933 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Please note that this site is covered in fewer than 80% of the individuals in Exac, and may represent a low quality site. A different variant at an adjacent base but the same codon, Arg35Trp, is also listed in ExAC, found in 5 of 22,239 people. Specifically, the variant was observed in 2 of 6436 South Asian people (AF: 0.015%) and 3 of 25,018 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 27707468, 24111713, 33782553, 35653365) -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 35 of the MYBPC3 protein (p.Arg35Gln). This variant is present in population databases (rs397515885, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 33782553). ClinVar contains an entry for this variant (Variation ID: 42503). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 29, 2024	This missense variant replaces arginine with glutamine at codon 35 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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: 24111713, 27532257, 32841044, 32815737, 33495596). It has also been reported in an individual affected with sudden unexplained nocturnal death (PMID: 27707468) and in an individual affected with familial stroke (PMID: 36580209). This variant has been identified in 16/241052 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. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 05, 2023

This missense variant replaces arginine with glutamine at codon 35 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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: 24111713, 27532257, 32841044, 32815737, 33495596). It has also been reported in an individual affected with sudden unexplained nocturnal death (PMID: 27707468) and in an individual affected with familial stroke (PMID: 36580209). This variant has been identified in 16/241052 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. -

Hypertrophic cardiomyopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

CardioboostCm

Uncertain

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.96

N;N;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.020

D;D;D

Sift4G

Uncertain

0.028

D;D;D

Polyphen

0.98

D;.;.

Vest4

0.77

MutPred

0.55

Loss of MoRF binding (P = 0.0352);Loss of MoRF binding (P = 0.0352);Loss of MoRF binding (P = 0.0352);

MVP

0.85

MPC

0.66

ClinPred

0.17

GERP RS

3.4

Varity_R

0.23

gMVP

0.39

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