11-47351481-C-T

Position:

• chr11-47351481-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000256.3(MYBPC3):​c.50G>A​(p.Arg17Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000578 in 1,590,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R17W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 4.63

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22598496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.50G>A	p.Arg17Gln	missense_variant	2/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.50G>A	p.Arg17Gln	missense_variant	2/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.50G>A	p.Arg17Gln	missense_variant	2/34	5		A2
MYBPC3	ENST00000544791.1	c.50G>A	p.Arg17Gln	missense_variant, NMD_transcript_variant	2/27	5

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

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: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000848 AC: 20 AN: 235814 Hom.: 0 AF XY: 0.0000621 AC XY: 8 AN XY: 128878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000297

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: 0.0000943

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000535 AC: 77 AN: 1438260 Hom.: 0 Cov.: 35 AF XY: 0.0000506 AC XY: 36 AN XY: 710816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000636

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000356

Gnomad4 OTH exome AF: 0.000135

GnomAD4 genome AF: 0.0000984 AC: 15 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74514

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	Variant summary: MYBPC3 c.50G>A (p.Arg17Gln) results in a conservative amino acid change located in the Immunoglobulin subtype (IPR003599) of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 235814 control chromosomes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.50G>A has been reported in the literature in individuals affected with Cardiomyopathy, however not all the information was provided for further analysis (example, McGurk_2023, Ochoa_2018, Pottinger_2020, Viswanathan_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated 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: 37652022, 30442288, 32009526, 29121657). ClinVar contains an entry for this variant (Variation ID: 164160). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2013	The Arg17Gln variant in MYBPC3 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8408 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The affected amino acid is not well conserved in evolution, suggesting that a change may be tolerated. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. At this time, additional information is needed to fully asses s the clinical significance of this variant. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 13, 2023	This missense variant replaces arginine with glutamine at codon 17 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 25342278, 28356264, 28771489, 29121657, 30442288, 34555931), in one individual with dilated cardiomyopathy (PMID: 30871747), and in two related individuals who were reported to be normal (PMID: 34555931). One of the affected probands also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 34555931). This variant has also been identified in 20/235814 chromosomes (10/33652 Latino chromosomes, 0.0297%) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals and has also been observed at an elevated allele frequency in the general population. 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	Aug 17, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2018	The R17Q variant of uncertain significance in the MYBPC3 gene has previously been reported in one patient with HCM with no family history of the disease, but was also present in 1/200 healthy control individuals (Garcia-Castro et al., 2008). This variant has been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiac genetic testing at GeneDx; however, thus far, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. This variant is observed in 9/32876 (0.03%) alleles from individuals of Latino ancestry and in 9/105042 (0.01%) alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the R17Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 10, 2020	- -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with glutamine at codon 17 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 25342278, 28356264, 28771489, 29121657, 30442288, 34555931), in one individual with dilated cardiomyopathy (PMID: 30871747), and in two related individuals who were reported to be normal (PMID: 34555931). One of the affected probands also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 34555931). This variant has also been identified in 20/235814 chromosomes (10/33652 Latino chromosomes, 0.0297%) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals and has also been observed at an elevated allele frequency in the general population. 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	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 17 of the MYBPC3 protein (p.Arg17Gln). This variant is present in population databases (rs374630007, gnomAD 0.03%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25342278, 29121657, 30871747; Invitae). ClinVar contains an entry for this variant (Variation ID: 164160). 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The p.R17Q variant (also known as c.50G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 50. The arginine at codon 17 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM); however, clinical details were limited and additional alterations in other cardiac-related genes were identified in some cases (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56; Alfares AA et al. Genet Med. 2015 Nov;17(11):880-8; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139; Helms AS at al. Circ Genom Precis Med. 2020 Oct;13(5):396-405). This variant was detected in both affected and unaffected relatives in a family with HCM (Dias GM et al. Circ Genom Precis Med. 2021 Oct;14(5):e003476). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	0.13
CardioboostCm	Benign	0.030
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	0.015
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.75	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.87	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.92	P;.;.
Vest4		0.44
MVP		0.85
MPC		0.54
ClinPred		0.17	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs374630007; hg19: chr11-47373032;