11-47335077-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000256.3(MYBPC3):c.2870C>G(p.Thr957Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,595,244 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:12
• Conservation: PhyloP100: 1.07

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02241832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2870C>G	p.Thr957Ser	missense_variant	27/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2870C>G	p.Thr957Ser	missense_variant	27/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2870C>G	p.Thr957Ser	missense_variant	26/34	5		A2

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 132 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00101 AC: 237 AN: 235526 Hom.: 0 AF XY: 0.00110 AC XY: 141 AN XY: 128316

Gnomad AFR exome AF: 0.000205

Gnomad AMR exome AF: 0.000649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.000354

GnomAD4 exome AF: 0.00170 AC: 2459 AN: 1442890 Hom.: 4 Cov.: 31 AF XY: 0.00161 AC XY: 1150 AN XY: 716100

Gnomad4 AFR exome AF: 0.000336

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000836

Gnomad4 FIN exome AF: 0.000416

Gnomad4 NFE exome AF: 0.00202

Gnomad4 OTH exome AF: 0.00170

GnomAD4 genome AF: 0.000866 AC: 132 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.000832 AC XY: 62 AN XY: 74502

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.000865

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.000993 AC: 120

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2023	Variant summary: MYBPC3 c.2870C>G (p.Thr957Ser) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 235526 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2870C>G has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence for causality (e.g. Ehlermann_2008, Rodriguez-Garcia_2010, Gruner_2011, Olivotto_2011, Merlo_2013, Pugh_2014, Earle_2015, Haas_2015, Medeiros-Domingo_2017, Mazzarotto_2019, Khan_2022). The variant did not segregate with disease in two cardiomyopathy families (internal testing). At least one co-occurrence with a pathogenic variant has been reported in the literature (TTN [NM_001256850.1] c.102712C>T, p.Gln34238X; Khan_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 19, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr957Ser (T957S; c.2870C>G) in exon 27 of the gene MYBPC3 (NM_000256.3) We re-reviewed the variant on 8/17/2015 and conclude it is variant of uncertain significance, but probably benign. In summary, the reasons for this are: Disease-causing variants in MYBPC3 are more likely to be truncating than missense; this missense variant is at a non-conserved residue and Serine is the standard amino acid in at least two species; the variant is more common in the Caucasian population than HCM. Thr957Ser in the MYBPC3 gene has been reported previously in at least 4 unrelated individuals with HCM, including as a VUS (Ehlermann et al. 2008, Rodriguez-Garcia et al. 2010, Olivotto et al. 2011, Gruner et al. 2011). There is no segregation data available in these papers. Ehlermann et al. reported it in one patient with HCM and did not observe it in 430 control individuals. Rodriguez-Garcia found it in one individual with HCM but reported it to have an uncertain pathogenic effect. Olivotto et al. reported it in one patient with HCM. Gruner et al. identified it in an individual with apical HCM and classified it as a VUS. In ClinVar, the Laboratory for Molecular Medicine (LMM) reports that it has identified this variant in 14 adults with HCM or DCM. However, they add, 5 of these individuals carried another variant sufficient to explain their disease. Thr957Ser results in a conservative amino acid change of a neutral, polar Threonine with a neutral, polar Serine at a position that is not conserved across species. In fact, the default amino acid is Serine in two species, according to LMM, supporting the idea that a Serine at this position may be tolerated. A variant at a neighboring residue (Thr958Ile) has been reported in association with HCM as have the variants Asn948Thr and Pro961Leu (Stenson et al. 2003), supporting the potential functional importance of this region of the protein. However, the NHLBI ESP Variant Server reports Thr957Ser in 11 out of 8,273 alleles from individuals of European background, indicating that it may be a benign variant. The ESP dataset currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Variation at this codon has also been seen frequently in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian) and includes ESP data. These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. It is present in 118/54,031 individuals overall, and 98/33,813 Caucasian individuals (our patient is Caucasian); this variant’s allele frequency is therefore over 0.1% among Caucasians, which means it would be present in 0.29% of the population=1/345 individuals. This is greater than the overall prevalence of HCM itself, which is why we suspect the variant is probably benign. In summary, with the clinical and molecular information available at this time we cannot determine whether this variant is a disease-causing mutation or a benign variant—but it seems more likely to be benign. The variant is not appropriate for predictive testing in family members, and no conclusions can be drawn about a patient’s risk for HCM based on this variant. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2017	The p.Thr957Ser variant in MYBPC3 has been reported in individuals with HCM (Ehl ermann 2008, Rodriguez-Garcia 2010, Olivotto 2011, Gruner 2011) and DCM (Merlo 2 013) but has also identified in 0.2% (187/120848) of European chromosomes by the gnomAD (gnomad.broadinstitute.org; dbSNP rs193922380). Threonine (Thr) at posit ion 957 is not conserved in evolution and 2 species (Chinese tree shrew and Mexi can tetra) carry a serine (Ser) at this position, supporting that a change at th is position may be tolerated. In summary, while the clinical significance of the p.Thr957Ser variant is not conclusive, these data suggest that it is likely ben ign. -

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	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: 20433692, 21511876, 20474083, 29710196, 22958901, 24119082, 23861362, 24055113, 23299917, 25637381, 25569433, 27194543, 29121657, 24503780, 28679633, 18957093, 22267749, 21835320, 33232181) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	MYBPC3: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Hypertrophic cardiomyopathy 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 13, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 06, 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. -

Primary familial hypertrophic cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 02, 2017	- -

Left ventricular noncompaction 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Aug 13, 2015

- -

Primary dilated cardiomyopathy Benign:1

Benign, no assertion criteria provided

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Dec 05, 2019

MYBPC3 Thr957Ser is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.0009. In silico tools SIFT, PolyPhen-HCM and MutationTaster predict this variant to be benign. We have identified MYBPC3 Thr957Ser in a proband who was diagnosed at with DCM and LVNC at birth. Familial segregation within this family revealed 2 affected family members who do have MYBPC3 Thr957Ser, but harbour a pathogenic TNNT2 variant. In summary, we have classified the MYBPC3 Thr957Ser variant as "Benign" based on its frequency in the general population, prediction of in silico tool, and the lack of segregation in our family. -

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

May 25, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
CardioboostCm	Benign	0.00078
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	15
Dann	Benign	0.89
DEOGEN2	Benign	0.38	T;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.42	T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.20	T;T;T
Vest4		0.67
MVP		0.75
MPC		0.20
ClinPred		0.024	T
GERP RS		0.79
Varity_R		0.13
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs193922380; hg19: chr11-47356628; COSMIC: COSV57027162; COSMIC: COSV57027162;