rs752200396

chr11-47338652-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3 PP5

The NM_000256.3(MYBPC3):c.2176C>T(p.Arg726Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,442 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R726H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:9
• Conservation: PhyloP100: 9.60

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 4 ACMG points.

• PM1: In a domain Ig-like C2-type 5 (size 126) in uniprot entity MYPC3_HUMAN there are 50 pathogenic changes around while only 6 benign (89%) in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 11-47338652-G-A is Pathogenic according to our data. Variant chr11-47338652-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575705.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=9}. Variant chr11-47338652-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2176C>T	p.Arg726Cys	missense_variant	23/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2176C>T	p.Arg726Cys	missense_variant	23/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2176C>T	p.Arg726Cys	missense_variant	22/34	5		A2
MYBPC3	ENST00000544791.1	c.2176C>T	p.Arg726Cys	missense_variant, NMD_transcript_variant	23/27	5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000606 AC: 15 AN: 247584 Hom.: 0 AF XY: 0.0000744 AC XY: 10 AN XY: 134422

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461276 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 726896

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74332

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.0000765 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2020	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 575705; Landrum et al., 2016); 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: 20594303, 19150014, 22765922, 22958901) -
Likely pathogenic, flagged submission	clinical testing	Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	Feb 02, 2022	- -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2023	This missense variant replaces arginine with cysteine at codon 726 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 individuals affected with hypertrophic cardiomyopathy (PMID: 22765922, 27930701), in an individual affected with noncompaction cardiomyopathy (PMID: 35885957), in an individual affected with Tetralogy of Fallot and multiple congenital anomalies (PMID: 35885957), and in an individual affected with sudden cardiac death (PMID: 32917565, 33919104). It has also been reported in an asymptomatic individual (PMID: 19150014). This variant has been identified in 16/278974 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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 12, 2021	- -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 09, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 726 of the MYBPC3 protein (p.Arg726Cys). This variant is present in population databases (rs752200396, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19150014). ClinVar contains an entry for this variant (Variation ID: 575705). 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 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with cysteine at codon 726 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 individuals affected with hypertrophic cardiomyopathy (PMID: 22765922, 27930701), in an individual affected with noncompaction cardiomyopathy (PMID: 35885957), in an individual affected with Tetralogy of Fallot and multiple congenital anomalies (PMID: 35885957), and in an individual affected with sudden cardiac death (PMID: 32917565, 33919104). It has also been reported in an asymptomatic individual (PMID: 19150014). This variant has been identified in 16/278974 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. -

Left ventricular noncompaction 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud

Feb 02, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 14, 2023

Variant summary: MYBPC3 c.2176C>T (p.Arg726Cys) results in a non-conservative amino acid change located in the immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 247584 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (6.1e-05 vs 0.001), allowing no conclusion about variant significance. c.2176C>T has been reported in the literature in the heterozygous state in an individual affected with hypertrophic cardiomyopathy who was subsequently cited by others (Garcia-Castro_2009, Coto_2012, Gomez_2017), in two cases of sudden unexplained death, one of which was likely attributed to dilated cardiomyopathy (Sanchez_2016) and the other with no conclusive cardiac-related cause (Iglesias_2021), and in two unrelated individuals undergoing genetic testing for congenital abnormalities, one with noncompaction cardiomyopathy and one with multiple congenital abnormalities including Tetralogy of Fallot, both of whom inherited the variant from a presumably unaffected parent (Delea_2022). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22765922, 35885957, 19150014, 28356264, 33919104, 35629155, 27930701). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

Hypertrophic cardiomyopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.2176C>Tp.Arg726Cys in MYBPC3 gene has been reported in individuals affected with hypertrophic cardiomyopathy Sanchez et. al., 2016; Coto et. al., 2012, as well as in an asymptomatic individual García-Castro et. al., 2009. This variant has been reported in one case with sudden cardiac death Ripoll-Vera et. al., 2021. The p.Arg726Cys variant is novel not in any individuals in 1000 Genomes and has allele frequency of 0.006% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Uncertain Significance. The amino acid change p.Arg726Cys in MYBPC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 726 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance VUS. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2023

The p.R726C variant (also known as c.2176C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2176. The arginine at codon 726 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in individuals with varying phenotypes including hypertrophic cardiomyopathy, dilated cardiomyopathy, sudden unexplained death, congenital heart disease, and noncompaction cardiomyopathy (Coto E et al. J Transl Med, 2010 Jul;8:64; Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Iglesias M et al. J Clin Med, 2021 Apr;10; Delea M et al. Genes (Basel), 2022 Jun;13). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Benign	0.24
CardioboostCm	Benign	0.0029
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.014	D
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.89
MVP		0.94
MPC		0.92
ClinPred		0.61	D
GERP RS		5.4
Varity_R		0.45
gMVP		0.64

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: rs752200396; hg19: chr11-47360203; COSMIC: COSV57022678;