rs199865688

chr11-47337496-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM5 BP4_Moderate

The NM_000256.3(MYBPC3):c.2497G>A(p.Ala833Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,052 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign 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. A833V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:16
• Conservation: PhyloP100: 2.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 50 pathogenic changes around while only 6 benign (89%) in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47337495-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.09121233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2497G>A	p.Ala833Thr	missense_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2497G>A	p.Ala833Thr	missense_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2497G>A	p.Ala833Thr	missense_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.*2G>A		3_prime_UTR_variant, NMD_transcript_variant	25/27	5

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152250 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00150 AC: 373 AN: 249150 Hom.: 0 AF XY: 0.00138 AC XY: 187 AN XY: 135146

Gnomad AFR exome AF: 0.000516

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00185 AC: 2703 AN: 1461684 Hom.: 6 Cov.: 33 AF XY: 0.00185 AC XY: 1344 AN XY: 727132

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00225

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152368 Hom.: 0 Cov.: 31 AF XY: 0.00115 AC XY: 86 AN XY: 74514

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00176 AC: 15

ExAC AF: 0.00168 AC: 203

EpiCase AF: 0.00158

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:7

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2022	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 11, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypertrophic cardiomyopathy 4 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 22, 2018	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. -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2018	- -

Primary familial hypertrophic cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Cardiomyopathy, dilated, 1MM Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2010

- -

Left ventricular noncompaction 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 21, 2018

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 27, 2015

p.Ala833Thr in exon 25 of MYBPC3: The significance of this variant was initially debated, as it was reported in 4 individuals with HCM, 3 of whom carried a seco nd variant (Morner 2003, Alders 2003, Andersen 2004, Van Driest 2004). Our labor atory has identified this variant in multiple individuals with various types of cardiomyopathies (HCM, DCM, and LVNC), some of whom also carried a second varian t. The frequent occurrence of a variant in conjunction with additional disease-c ausing variants argues against a pathogenic role when present in isolation as do es its identification in individuals with HCM, LVNC and DCM as these cardiomyopa thies are caused by different defects at the cellular level. Finally, this varia nt has been identified in 0.2% (182/66666) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199865688) . In summary, the overall evidence suggests that the p.Ala833Thr variant is like ly benign, though we cannot rule out that it may modify disease severity when pr esent with other cardiomyopathy variants. -

Primary dilated cardiomyopathy Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 04, 2014

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

This alteration is classified as likely 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. -

Paroxysmal atrial fibrillation Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 04, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Benign	0.28
Sift	Benign	0.044	D;.;D
Sift4G	Uncertain	0.038	D;D;D
Vest4		0.65
MVP		0.91
MPC		0.80
ClinPred		0.050	T
GERP RS		4.6
Varity_R		0.26
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

Other links and lift over

dbSNP: rs199865688; hg19: chr11-47359047;