11-47351308-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000256.3(MYBPC3):c.223G>A(p.Asp75Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,578,354 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:10

Conservation

PhyloP100: 7.38

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 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.223G>A	p.Asp75Asn	missense_variant	Exon 2 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.223G>A	p.Asp75Asn	missense_variant	Exon 2 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.223G>A	p.Asp75Asn	missense_variant	Exon 2 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.223G>A		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000152

AC:

AN:

197134

Hom.:

AF XY:

0.0000282

AC XY:

AN XY:

106472

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:

0.0000351

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1425996

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

705752

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000534

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000293

Gnomad4 OTH exome

AF:

0.0000847

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000335

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000331

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:3

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 75 of the MYBPC3 protein (p.Asp75Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 21488259, 21943931, 27600940, 28771489, 30871747, 31513939). ClinVar contains an entry for this variant (Variation ID: 161313). 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. -

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 75 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 at least 3 individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 27600940, 31513939), as well as in a healthy control subject (PMID: 20433692). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has been identified in 4/228528 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. -

Feb 09, 2017

Center for Human Genetics, University of Leuven

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG score unknown significance -

Hypertrophic cardiomyopathy 4

Pathogenic:1Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jul 12, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp75Asn variant in MYBCP3 has been reported in 6 individuals with HCM and 1 individual with DCM (Rodriguez-Garcia 2010, Lakdawala 20111, Cecconi 2016, Mademont-Soler 2017, Walsh 2017, Wiffin 207, Sousa 2019). One individual with HCM carried an additional pathogenic variant in MYBPC3 (Mademont-Soler 2017). It has also been identified in 4/100946 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3. -

Cardiomyopathy

Uncertain:1

Sep 30, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Uncertain:1

Jan 03, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with HCM, though many publications did not include patient-specific clinical details (Harris et al., 2011; Lakdawala et al., 2011; Andreasen et al., 2013; Amendola et al., 2015; Ho et al., 2015; Cecconi et al., 2016; Ito et al., 2017; Walsh et al., 2017); Reported in a 12-year-old Spanish female with HCM who also harbored a pathogenic MYBPC3 splice site variant (Mademont-Soler et al., 2017); Segregation studies in a family with HCM revealed this variant in one possibly affected family member and one family member with a normal phenotype, whereas the variant was absent in a family member with suggestive electrocardiographic alterations (Rodriguez-Garcia et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31513939, 30871747, 23299917, 25637381, 21488259, 27532257, 21943931, 28679633, 28771489, 27600940, 25543971, 21415409, 28518168) -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype

Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D75N variant (also known as c.223G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 223. The aspartic acid at codon 75 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cohorts (Lopes LR et al. Heart, 2015 Feb;101:294-301; Rodríguez-García MI et al. BMC Med Genet, 2010 Apr;11:67; Lakdawala NK et al. Am J Cardiol, 2011 Dec;108:1606-13; Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Sousa A et al. Rev Port Cardiol (Engl Ed), 2019 Feb;38:129-139; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet, 2013 Sep;21:918-28). This amino acid position is highly 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. -

MYBPC3-related disorder

Uncertain:1

Oct 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYBPC3 c.223G>A variant is predicted to result in the amino acid substitution p.Asp75Asn. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Rodríguez-García et al. 2010. PubMed ID: 20433692; Supplemental Table in Lakdawala et al. 2011. PubMed ID: 21943931; Supplemental Table 2 in Mademont-Soler et al. 2017. PubMed ID: 28771489; Sousa et al. 2018. PubMed ID: 30871747; Supplemental Table 2 in Robyns et al. 2020. PubMed ID: 31513939). In one study, analysis of the proband's family, was not fully supportive for segregation (Rodríguez-García et al. 2010. PubMed ID: 20433692). This variant is reported in 0.0040% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47372859-C-T). In ClinVar, this variant has been interpreted as uncertain by the majority of submitting laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/161313/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

CardioboostCm

Benign

0.042

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.5

H;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

N;N;N

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.026

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.90

MVP

0.92

MPC

0.82

ClinPred

0.91

GERP RS

4.3

Varity_R

0.75

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