chr11-47352635-C-G

Position:

• chr11-47352635-C-G

Variant summary

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

The NM_000256.3(MYBPC3):​c.13G>C​(p.Gly5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000835 in 1,596,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:5
• Conservation: PhyloP100: 1.88

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=0.03770563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.13G>C	p.Gly5Arg	missense_variant	1/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.13G>C	p.Gly5Arg	missense_variant	1/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.13G>C	p.Gly5Arg	missense_variant	1/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.13G>C	p.Gly5Arg	missense_variant, NMD_transcript_variant	1/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000985

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000298 AC: 69 AN: 231870 Hom.: 0 AF XY: 0.000340 AC XY: 43 AN XY: 126622

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000641

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: 0.000558

Gnomad OTH exome AF: 0.000183

GnomAD4 exome AF: 0.000868 AC: 1254 AN: 1444702 Hom.: 1 Cov.: 30 AF XY: 0.000881 AC XY: 633 AN XY: 718662

Gnomad4 AFR exome AF: 0.000216

Gnomad4 AMR exome AF: 0.0000705

Gnomad4 ASJ exome AF: 0.0000781

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.000956

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74418

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000547 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000763 AC: 3

ESP6500EA AF: 0.000842 AC: 7

ExAC AF: 0.000298 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:9 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 12, 2017	Patient is a teenage Caucasian male with a recent history of palpitations and a diagnosis of LVNC on cardiac MRI, but with normal biventricular size and function. Genetic testing was done at Invitae laboratory. p.Gly5Arg (G5R; c.13G>C) in exon 1 of the MYBPC3 gene (NM_000256.3) Chromosome location 11:47374186 C / G Based on the information reviewed below, we classify this as a variant of uncertain significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk family members. In summary, this variant has been reported in several individuals with various cardiomyopathies, yet a fair number of those individuals also carry a second pathogenic variant sufficient to explain their disease. There is only very weak published segregation data: specifically, segregating in one family member with a borderline phenotype in just one family (Villacorta et al. 2014). Furthermore, Gly5Arg is found in the population at an appreciable frequency, and changes a residue that is not well conserved across species. For those reasons, we think it is unlikely to cause disease. The Gly5Arg variant has been reported in at least 7 individuals with various forms of cardiomyopathy (5 HCM, 1 DCM, 1 LVNC). Of note: Three of the individuals with HCM also had a separate, convincingly pathogenic variant in MYBPC3. Van Driest et al. (2004) reported the variant in a proband with HCM who also had a pathogenic Arg502Trp variant in the MYBPC3 gene. Keeling et al. (2010) reported it in one individual with HCM (septal thickness 2.2 cm). Berge & Loren (2014) reported it in two Norwegian probands with HCM, one of whom also had a pathogenic truncating variant in MYBPC3 (Ser311*). Villacorta et al. from Spain reported it in a woman with HCM who also had a truncating variant in MYBPC3 in trans: Asn1023fs+28*. The truncating variant segregated with disease in the patient’s 37-year-old affected brother (septal thickness 1.9 cm, cardiac fibrosis on MRI) while Gly5Arg was not present in him. Their father, who at age 63 had borderline septal hypertrophy of 1.6 cm, a PW thickness of 1.0 cm, and a history of hypertension, had the Gly5Arg variant (which the authors interpreted as disease-causing). Their mother had the truncating variant and a normal echocardiogram. Hershberger et al. reported it in a patient with familial DCM, however no family members were available for segregation analysis. Probst et al. (2011) reported it in a proband with chest pain and left ventricular non-compaction (LVNC) as well as the patient’s 47-year-old unaffected mother. In addition, Morita et al. (2006) reported the variant in a participant in the Framingham Heart Study who had somewhat increased left ventricular wall thickness of >1.3 cm but no known diagnosis of HCM; it was also present in an elderly sibling with normal LV wall thickness. This is a non-conservative amino acid change, resulting in the replacement of a nonpolar Glycine with a positively-charged Arginine. Glycine at this location is not well conserved across vertebrate species. It is frequently an Alanine, Valine, or Threonine instead. Arginine is, in fact, the default amino acid in at least one mammalian species. LMM reports that the change to Arginine was predicted to be benign using their computational tool clinically validated for HCM variants. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). Loss of function variants, such as protein-truncating variants, in the MYBPC3 gene are a well-known cause of cardiomyopathy, while certain missense variants may be tolerated. One experimental study suggests that the Gly5Arg missense change does not have an effect on MYBPC3 protein binding to myosin (Ratti et al. 2011). In total the variant has been seen in at least 85 of 131,396 published controls and individuals from publicly available population datasets. The variant was not observed in 926 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2021	The MYBPC3 c.13G>C, p.Gly5Arg variant (rs201278114) is reported in the literature in individuals affected with hypertrophic cardiomyopathy (Berge 2014, Van Driest 2004, Villacorta 2014), dilated cardiomyopathy (Hershberger 2010), and LVNC (Probst 2011). However, this variant was found to co-occur with an additional pathogenic MYBPC3 variant in two cases (Van Driest 2004, Villacorta 2014). One functional study demonstrated the variant protein maintains wild type binding to Fhod3 (Matsuyama 2018). This variant is also reported in ClinVar (Variation ID: 161305) and is found in the non-Finnish European population with an allele frequency of 0.06% (73/121166 alleles) in the Genome Aggregation Database. The glycine at codon 5 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.186). Due to limited information, the clinical significance of the p.Gly5Arg variant is uncertain at this time. References: Berge KE, Leren TP. Genetics of hypertrophic cardiomyopathy in Norway. Clin Genet. 2014 Oct;86(4):355-60. PMID: 24111713. Hershberger RE et al. Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circ Cardiovasc Genet. 2010 Apr;3(2):155-61. PMID: 20215591. Matsuyama S et al. Interaction between cardiac myosin-binding protein C and formin Fhod3. Proc Natl Acad Sci U S A. 2018 May 8;115(19):E4386-E4395. PMID: 29686099. Probst S et al. Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. Circ Cardiovasc Genet. 2011 Aug 1;4(4):367-74. PMID: 21551322. Van Driest SL et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Nov 2;44(9):1903-10. PMID: 15519027. Villacorta E et al. Usefulness of genetic diagnosis in a woman with hypertrophic cardiomyopathy and the desire for motherhood. Rev Esp Cardiol (Engl Ed). 2014 Feb;67(2):148-50. PMID: 24795128. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MYBPC3: BP4, BP5 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2022	See Variant Classification Assertion Criteria. -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 5 of the MYBPC3 protein (p.Gly5Arg). This variant is present in population databases (rs201278114, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC) (PMID: 15519027, 21551322, 24111713, 24795128). ClinVar contains an entry for this variant (Variation ID: 161305). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect MYBPC3 function (PMID: 21297165). 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 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 24, 2020	Variant summary: MYBPC3 c.13G>C (p.Gly5Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 232870 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (0.0003 vs 0.001), allowing no conclusion about variant significance. c.13G>C has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, left ventricular non-compaction, as well as in unaffected individuals (Van Driest_2004, Morita_2006, Keeling_2010, Probst_2011, Berge_2013, Villacorta_2013, Pugh_2014, Methner_2016, Gomez_2017, Ko_2017, Norrish_2019). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic MYBPC3 variants have been reported (MYBPC3 c.1504C>T, p.Arg502Trp; MYBPC3 c.3066dupC, p.N1023fs*28) (Van Driest_2004, Villacorta_2013), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Matsuyama_2018). Ten ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x), uncertain significance (7x) and pathogenic (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2018	The p.Gly5Arg variant in MYBPC3 is classified as likely benign because it has be en identified in 0.06% (75/120166) of European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201278114). Pl ease note: this variant has been reported in individuals with various cardiomyop athies (8 HCM/LVH, 2 DCM, 1 LVNC; Berge 2014, Hershberger 2010, Keeling 2010, M orita 2006, Probst 2011, Van Driest 2004, Villacorta 2014, LMM data). Due to the frequency of this variant, it would be expected, by chance, that some individua ls with cardiomyopathy may carry this variant. Furthermore, four of the individu als with HCM described above also carried pathogenic loss-of-function variants i n the MYBPC3 gene, sufficient to explain their cardiomyopathy (Berge 2014, Van D riest 2004, Villacorta 2014, LMM data). ACMG/AMP Criteria applied: BS1; BP5. -

Cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 28, 2019	- -

Left ventricular hypertrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Mar 28, 2015

- -

Hypertrophic cardiomyopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2021

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	0.25
CardioboostCm	Benign	0.0057
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.095	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.23	B;.;.
Vest4		0.25
MutPred		0.71		Gain of MoRF binding (P = 0.0187);Gain of MoRF binding (P = 0.0187);Gain of MoRF binding (P = 0.0187);
MVP		0.73
MPC		0.42
ClinPred		0.086	T
GERP RS		4.5
Varity_R		0.19
gMVP		0.27

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: rs201278114; hg19: chr11-47374186;