Submissions for variant NM_000256.3(MYBPC3):c.3103G>A (p.Ala1035Thr)

gnomAD frequency: 0.00002  dbSNP: rs552505566

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001056384	SCV001220825	uncertain significance	Hypertrophic cardiomyopathy	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1035 of the MYBPC3 protein (p.Ala1035Thr). This variant is present in population databases (rs552505566, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27600940, 30847666). ClinVar contains an entry for this variant (Variation ID: 188575). 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 tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV001178568	SCV001343039	uncertain significance	Cardiomyopathy	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1035 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27600940, 30847666). This variant has been identified in 9/245694 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.
GeneDx	RCV001699214	SCV001988391	uncertain significance	not provided	2020-12-17	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 188575; Landrum et al., 2016); 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: 27600940, 30847666)
Ambry Genetics	RCV003362705	SCV004084401	uncertain significance	Cardiovascular phenotype	2023-07-21	criteria provided, single submitter	clinical testing	The p.A1035T variant (also known as c.3103G>A), located in coding exon 29 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3103. The alanine at codon 1035 is replaced by threonine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) or HCM genetic testing cohorts; however, details were limited (Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant co-occurred with a variant in the TGFBR2 gene in an infant with features of Loeys-Dietz syndrome, seizures, biventricular HCM, and aortic coarctation (Akbar A et al. BMJ Case Rep, 2022 Nov;15). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genetics, Academic Medical Center	RCV001699214	SCV001922420	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001699214	SCV001975471	uncertain significance	not provided		no assertion criteria provided	clinical testing