Submissions for variant NM_000256.3(MYBPC3):c.659A>G (p.Tyr220Cys)

gnomAD frequency: 0.00003  dbSNP: rs779693951

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414208	SCV000490634	uncertain significance	not specified	2016-11-09	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The c.659 A>G (Y220C) variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been observed in one other unrelated individual referred for HCM genetic testing at GeneDx. However, segregation information is uninformative. The c.659 A>G (Y220C) variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. At the protein level, the c.659 A>G (Y220C) 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. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. At the mRNA level, this substitution occurs at a nucleotide that is conserved across species, and two in silico splice prediction programs predict this variant may result in the creation of a cryptic splice donor site. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV000628903	SCV000749811	uncertain significance	Hypertrophic cardiomyopathy	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 220 of the MYBPC3 protein (p.Tyr220Cys). This variant is present in population databases (rs779693951, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 29524613, 29907873, 34011823). ClinVar contains an entry for this variant (Variation ID: 372419). 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. Studies have shown that this missense change does not affect mRNA splicing (PMID: 28679633). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170210	SCV001332762	uncertain significance	Cardiomyopathy	2019-03-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170210	SCV001353550	uncertain significance	Cardiomyopathy	2022-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 220 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A mini-gene assay showed that this variant did not alter RNA splicing (PMID: 34097875). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 29524613); this individual also carried a pathogenic variant in the MYBPC3 gene that could explain the observed phenotype. The individual's parent also carried this variant and was asymptomatic. This variant has been identified in 6/275568 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.