rs397515923

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_000256.3(MYBPC3):​c.1766G>A​(p.Arg589His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000038 in 1,579,488 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R589G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

8
10
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 7.53
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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 chr11-47342016-G-C is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.1766G>A p.Arg589His missense_variant 18/35 ENST00000545968.6 NP_000247.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.1766G>A p.Arg589His missense_variant 18/355 NM_000256.3 ENSP00000442795 P4Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.1766G>A p.Arg589His missense_variant 17/345 ENSP00000382193 A2
MYBPC3ENST00000544791.1 linkuse as main transcriptc.1766G>A p.Arg589His missense_variant, NMD_transcript_variant 18/275 ENSP00000444259

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD3 exomes
AF:
0.0000102
AC:
2
AN:
196408
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
105382
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000359
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:
0.0000119
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000280
AC:
4
AN:
1427286
Hom.:
0
Cov.:
32
AF XY:
0.00000141
AC XY:
1
AN XY:
706760
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000260
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:
0.00000274
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
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:
0.00
Alfa
AF:
0.0000680
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000249
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 15, 2023Present in an infant with severe HCM who had two other pathogenic variants in the MYBPC3 gene; the R589H variant was found to be on the same allele as the c.3288delG frameshift pathogenic variant (Lekanne Deprez et al., 2006); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 27532257, 30847666, 16679492, 21750094, 28138913) -
Uncertain significance, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsFeb 10, 2022- -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Hypertrophic cardiomyopathy Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 589 of the MYBPC3 protein (p.Arg589His). 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 individual(s) with hypertrophic cardiomyopathy (PMID: 16679492, 21750094, 27476098, 27532257). ClinVar contains an entry for this variant (Variation ID: 42563). 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. This variant disrupts the p.Arg589 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 30105547), which suggests that this may be a clinically significant amino acid residue. 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 submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 18, 2023This missense variant replaces arginine with histidine at codon 589 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 21750094, 27476098, 27532257, 30297972, 34389451; Makul, 2019, DOI: 10.1016/j.bpj.2018.11.1424). This variant has also been reported in a neonate with hypertrophic cardiomyopathy, who carried another pathogenic truncation variant in the same gene that could explain the observed disease (PMID: 16679492). This variant has been identified in 2/196408 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 submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoApr 01, 2019- -
not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 06, 2014The Arg589His variant in MYBPC3 has been identified in 4 individuals with HCM (1 infant, 1 child, 2 adults), three of whom carried other pathogenic variants in MYBPC3 (Lekanne Deprez 2006, Waldmuller 2011, LMM unpublished data). It was abse nt from large population studies. Computational prediction tools and conservatio n analysis do not provide strong support for or against an impact to the protein . In summary, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 01, 2020Variant summary: MYBPC3 c.1766G>A (p.Arg589His) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 196608 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1766G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy without strong evidence for causality (examples- Lekanne_2006, Waldmuller_2011, van Velzen_2017, Walsh_2017, Ho_2018). In at least one of these publications, the variant was detected in cis with another pathogenic variant (MYBPC3 c.3288delG, p.Glu1096AspfsX93; this patient also carried MYBPC3 c.2827C>T, p.Arg943X in trans- Lekanne_2006). Co-occurrence with MYBPC3 c.3288delG has also been reported in three samples tested in our laboratory (phase unknown), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS- possibly benign.. -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 02, 2023This missense variant replaces arginine with histidine at codon 589 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 21750094, 27476098, 27532257, 30297972, 34389451; Makul, 2019, DOI: 10.1016/j.bpj.2018.11.1424). This variant has also been reported in a neonate with hypertrophic cardiomyopathy, who carried another pathogenic truncation variant in the same gene that could explain the observed disease (PMID: 16679492). This variant has been identified in 2/196408 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. -
Hypertrophic cardiomyopathy 4 Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 29, 2016The p.R589H variant (also known as c.1766G>A), located in coding exon 18 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1766. The arginine at codon 589 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in two individuals with hypertrophic cardiomyopathy (HCM) (Lekanne Deprez RH, J. Med. Genet. 2006 Oct; 43(10):829-32; Waldmüller S, Eur. J. Heart Fail. 2011 Nov; 13(11):1185-92). One of these reports was in an infant with HCM who also carried a nonsense and a frameshift alteration in MYBPC3, which were inherited from unaffected parents (Lekanne Deprez RH, J. Med. Genet. 2006 Oct; 43(10):829-32). 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 variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
CardioboostCm
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.72
D;T;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.51
D
MetaRNN
Pathogenic
0.87
D;D;D
MetaSVM
Uncertain
0.27
D
MutationAssessor
Uncertain
2.8
M;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-4.4
D;.;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0050
D;.;D
Sift4G
Benign
0.077
T;T;T
Vest4
0.89
MVP
0.90
MPC
0.92
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.51
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397515923; hg19: chr11-47363566; API