rs730880624

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000256.3(MYBPC3):​c.709T>C​(p.Tyr237His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,330 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. Y237C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

12
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 7.46
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 Pathogenic. Variant got 11 ACMG points.

PM1
In a domain Ig-like C2-type 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-47348486-T-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 11-47348487-A-G is Pathogenic according to our data. Variant chr11-47348487-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181047.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=4}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.709T>C p.Tyr237His missense_variant 6/35 ENST00000545968.6 NP_000247.2 Q14896-1A5YM48

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.709T>C p.Tyr237His missense_variant 6/355 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.709T>C p.Tyr237His missense_variant 6/345 ENSP00000382193.2 A8MXZ9
MYBPC3ENST00000544791.1 linkuse as main transcriptn.709T>C non_coding_transcript_exon_variant 6/275 ENSP00000444259.1 F5GZR4

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461330
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726928
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 20, 2020Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID 181047; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28679633, 18258667) -
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 14, 2023The MYBPC3 c.709T>C; p.Tyr237His variant (rs730880624) is reported in the literature in individuals affected with hypertrophic cardiomyopathy (HCM) or left ventricular noncompaction (Schultze-Berndt 2021, Waldmuller 2008, Wang 2008). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.919). Additionally, other variants at this codon (c.710A>G; p.Tyr237Ser, c.710A>G; p.Tyr237Cys) have been reported in individuals with HCM (Coto 2012, Garcia-Castro 2009, Morner 2003, Walsh 2017). Based on available information, the p.Tyr237His variant is considered to be likely pathogenic. References: Coto E et al. Resequencing the whole MYH7 gene (including the intronic, promoter, and 3' UTR sequences) in hypertrophic cardiomyopathy. J Mol Diagn. 2012 Sep;14(5):518-24. PMID: 22765922. Garcia-Castro M et al. Espectro mutacional de los genes sarcoméricos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en pacientes con miocardiopatía hipertrófica [Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. Rev Esp Cardiol. 2009 Jan;62(1):48-56. Spanish. PMID: 19150014. Morner S et al. Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden. J Mol Cell Cardiol. 2003 Jul;35(7):841-9. PMID: 12818575. Schultze-Berndt A et al. Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy. Front Pediatr. 2021 Sep 3;9:722926. PMID: 34540771. Waldmuller S et al. Array-based resequencing assay for mutations causing hypertrophic cardiomyopathy. Clin Chem. 2008 Apr;54(4):682-7. PMID: 18258667. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. Wang J et al. Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. Eur J Heart Fail. 2014 Sep;16(9):950-7. PMID: 25132132. -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2016- -
Left ventricular noncompaction cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterresearchKlaassen Lab, Charite University Medicine Berlin-- -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 08, 2024The p.Y237H variant (also known as c.709T>C), located in coding exon 6 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 709. The tyrosine at codon 237 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in several individuals with hypertrophic cardiomyopathy (Waldmüller S et al. Clin. Chem. 2008;54:682-7; Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Ambry internal data; external communication). This alteration has also been reported in a left ventricular non-compaction cohort (Schultze-Berndt A et al. Front Pediatr, 2021 Sep;9:722926). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
MYBPC3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 14, 2023The MYBPC3 c.709T>C variant is predicted to result in the amino acid substitution p.Tyr237His. This variant has been reported in an individual with hypertrophic cardiomyopathy (Waldmuller et al. 2008. PubMed ID: 18258667) and an individual with left ventricular noncompaction (Table S1, Schultze-Berndt et al. 2021. PubMed ID: 34540771). Additionally, different missense variants affecting this amino acid (p.Tyr237Ser, p.Tyr237Cys) have been reported in individuals with hypertrophic cardiomyopathy (Table S1A/B – Walsh et al. 2017. PubMed ID: 27532257; García-Castro et al. 2009. PubMed ID: 19150014). Functional studies of the p.Tyr237Ser variant found it accelerates contractile function (Doh et al. 2019. PubMed ID: 30611859). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioFeb 12, 2021- -
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 21, 2023In 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. This variant disrupts the p.Tyr237 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12818575, 24111713, 27532257, 30611859). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 181047). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or left ventricular noncompaction cardiomyopathy (PMID: 18258667, 34540771; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 237 of the MYBPC3 protein (p.Tyr237His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
CardioboostCm
Benign
0.096
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D;T;T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Uncertain
2.6
M;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-4.4
D;D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.87
MutPred
0.98
Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);
MVP
0.95
MPC
0.58
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.73
gMVP
0.85

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

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

Other links and lift over

dbSNP: rs730880624; hg19: chr11-47370038; API