Variant chr11-47333201-T-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000256.3(MYBPC3):c.3323A>C(p.Lys1108Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000949 in 1,602,334 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 3.99

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3323A>C	p.Lys1108Thr	missense_variant	30/35	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.3323A>C	p.Lys1108Thr	missense_variant	30/35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3323A>C	p.Lys1108Thr	missense_variant	29/34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152154

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:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000394

AC:

AN:

228198

Hom.:

AF XY:

0.0000243

AC XY:

AN XY:

123592

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:

0.0000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000938

AC:

136

AN:

1450180

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

720090

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

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:

0.000119

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.000105

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74322

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:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces lysine with threonine at codon 1108 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 33495597), in one individual affected with arrhythmia (PMID: 26743238), and in one individual affected with dilated cardiomyopathy (PMID: 32746448). This variant has been identified in 16/259538 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1108 of the MYBPC3 protein (p.Lys1108Thr). This variant is present in population databases (rs397516015, gnomAD 0.01%). This missense change has been observed in individual(s) with arrhythmia and dilated cardiomyopathy, as well as in one individual without cardiomyopathy from the Framingham Offspring Study participants (PMID: 22958901, 26743238, 32746448). ClinVar contains an entry for this variant (Variation ID: 42704). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 19, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Lys1108Thr variant (MYBPC3) has not been reported in the literature nor previously identifi ed in >2000 Caucasian probands tested by our laboratory. Lysine (Lys) at postion 1108 is highly conserved through distantly related species and computational an alyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) sugge st that the Lys1108Thr variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. Although this data supports that the Lys1108Thr variant may be pathogenic, additional studies are needed to fully assess its clinical significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 13, 2023

This missense variant replaces lysine with threonine at codon 1108 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmia (PMID: 26743238) and in an individual affected with dilated cardiomyopathy (PMID: 32746448). This variant has been identified in 16/259538 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

Dec 17, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2024

Reported in individuals with HCM, sudden unexplained death and/or DCM in published literature and in patients referred to GeneDx for genetic testing; however clinical details and segregation studies are not available for the published cases (PMID: 29247119, 26743238, 32746448); 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: 26743238, 22958901, 28679633, 32746448, 29247119, 35653365, 37652022) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2023

The p.K1108T variant (also known as c.3323A>C), located in coding exon 30 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 3323. The lysine at codon 1108 is replaced by threonine, an amino acid with similar properties. This variant has been reported in an arrhythmia cohort and a sudden unexplained death case; however, clinical details were limited (Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:). This alteration has also been reported in a population-based longitudinal study in an individual without overt cardiomyopathy (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9). This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM); however, clinical data is limited and it was also reported in a control individual (Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405; Tadros R et al. Nat Genet, 2021 Feb;53:128-134; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Uncertain

0.40

CardioboostCm

Uncertain

0.28

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.5

M;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.3

D;.;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.60

MVP

0.86

MPC

0.89

ClinPred

0.73

GERP RS

4.2

Varity_R

0.53

gMVP

0.59

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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