rs201596087

Positions:

• chr11-47341992-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM5 PP3_Strong

The NM_000256.3(MYBPC3):​c.1789C>T​(p.Arg597Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000034 in 1,558,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. R597Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 0.1545
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10
• Conservation: PhyloP100: 3.70

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Ig-like C2-type 4 (size 89) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47341991-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1789C>T	p.Arg597Trp	missense_variant, splice_region_variant	18/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1789C>T	p.Arg597Trp	missense_variant, splice_region_variant	18/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1789C>T	p.Arg597Trp	missense_variant, splice_region_variant	17/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1789C>T		splice_region_variant, non_coding_transcript_exon_variant	18/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152018 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000297 AC: 5 AN: 168412 Hom.: 0 AF XY: 0.0000562 AC XY: 5 AN XY: 89020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000396

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: 0.0000591

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000320 AC: 45 AN: 1406648 Hom.: 0 Cov.: 32 AF XY: 0.0000317 AC XY: 22 AN XY: 694438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000554

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000388

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152018 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74234

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000291 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000340 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 09, 2021	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2018	The R597W variant in the MYBPC3 gene was shown to co-segregate with HCM in three related individuals (Serio et al, 2009). However, these individuals also harbored a M849C variant in MYH7 rendering the true significance of the variants unattainable from this source. Coppini et al. (2014) also reported R597W in an individual with HCM for whom no family history information was provided. The R597W variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the R597W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R597Q) and in a nearby residue (D604V) have been reported in the Human Gene Mutation Database (Stenson et al., 2014), but the full significance of these variants is unknown. Finally, this variant has been identified independently and/or in conjunction with additional variants in individuals referred for genetic testing at GeneDx for cardiomyopathy. Nevertheless, the information obtained from testing of these individuals is not sufficient, and additional family studies are essential for full interpretation.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 10, 2024	This missense variant replaces arginine with tryptophan at codon 597 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant.This variant has been reported in two unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 25524337, 27532257). This variant has been reported in another individual affected with HCM, who also carried a pathogenic truncation variant in the same gene (PMID: 30896616). Additionally, this variant has been reported in three related individuals from an Italian family affected with HCM, who also carried a variant of uncertain significance in the MYH7 gene (Serio 2009). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg597Gln, is a well documented pathogenic mutation (Clinvar variation ID: 164098), indicating that arginine at this position is important for MYBPC3 protein function. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 597 of the MYBPC3 protein (p.Arg597Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25524337, 27532257, 30896616, 33782553). ClinVar contains an entry for this variant (Variation ID: 179549). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 23, 2023

This missense variant replaces arginine with tryptophan at codon 597 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant.This variant has been reported in two unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 25524337, 27532257). This variant has been reported in another individual affected with HCM, who also carried a pathogenic truncation variant in the same gene (PMID: 30896616). Additionally, this variant has been reported in three related individuals from an Italian family affected with HCM, who also carried a variant of uncertain significance in the MYH7 gene (Serio 2009). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg597Gln, is a well documented pathogenic mutation (Clinvar variation ID: 164098), indicating that arginine at this position is important for MYBPC3 protein function. 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 30, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The p.R597W variant (also known as c.1789C>T), located in coding exon 18 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1789. The arginine at codon 597 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in a compound heterozygous individual with hypertrophic cardiomyopathy (HCM), who had an MYBPC3 frameshift variant in trans, and was also reported in two unaffected relatives, who were heterozygous for R597W only (Chen X et al. Medicine (Baltimore), 2019 Mar;98:e14676). In addition, this alteration has been reported in HCM cohorts; however, limited clinical information was provided (Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Uncertain	0.41
CardioboostCm	Uncertain	0.84
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	3.4	M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.8	D;.;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.97
MVP		0.93
MPC		0.84
ClinPred		0.87	D
GERP RS		4.2
Varity_R		0.78
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201596087; hg19: chr11-47363543;