Submissions for variant NM_000256.3(MYBPC3):c.481C>T (p.Pro161Ser)

dbSNP: rs397516053

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000602854	SCV000743582	pathogenic	Hypertrophic cardiomyopathy 4	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000602854	SCV000744879	pathogenic	Hypertrophic cardiomyopathy 4	2015-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001700169	SCV002525330	uncertain significance	not provided	2022-05-31	criteria provided, single submitter	clinical testing	Reported in multiple Dutch patients with cardiomyopathy or arrhythmia, but most affected individuals also harbored variants in other genes (Alders et al., 2003; Christiaans et al., 2010; Verhagen et al., 2018; van Lint et al., 2019); Not observed at 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: 21415409, 14563344, 22857948, 20019025, 29988065, 30847666)
Ambry Genetics	RCV002334031	SCV002638000	uncertain significance	Cardiovascular phenotype	2018-09-18	criteria provided, single submitter	clinical testing	The p.P161S variant (also known as c.481C>T), located in coding exon 4 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 481. The proline at codon 161 is replaced by serine, an amino acid with similar properties. This alteration has been previously reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Alders M et al. Eur. Heart J. 2003;24:1848-53; Brito D et al. Rev Port Cardiol. 2012;31:577-87). 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 alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531733	SCV003439705	uncertain significance	Hypertrophic cardiomyopathy	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 161 of the MYBPC3 protein (p.Pro161Ser). 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 individuals with hypertrophic cardiomyopathy (PMID: 14563344, 22857948, 30847666; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 518242). 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.Pro161 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (internal data), 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000602854	SCV000733074	pathogenic	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001700169	SCV001925498	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001700169	SCV001953254	likely pathogenic	not provided		no assertion criteria provided	clinical testing