rs730880624

Positions:

• chr11-47348487-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 7.46

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 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
MYBPC3	NM_000256.3	c.709T>C	p.Tyr237His	missense_variant	6/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.709T>C	p.Tyr237His	missense_variant	6/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.709T>C	p.Tyr237His	missense_variant	6/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.709T>C		non_coding_transcript_exon_variant	6/27	5		ENSP00000444259.1

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

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:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	Not 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 submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	The 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. -

Left ventricular noncompaction cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

-

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The 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 submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2023

The 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 submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 12, 2021

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 21, 2023

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. 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

Other links and lift over

dbSNP: rs730880624; hg19: chr11-47370038;