Submissions for variant NM_000256.3(MYBPC3):c.1543_1545del (p.Asn515del)

dbSNP: rs730880643

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158347	SCV000208282	uncertain significance	not provided	2018-12-24	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The c.1543_1545delAAC variant in the MYBPC3 gene has been reported previously in one individual with DCM (Waldmuller et al., 2011). The c.1543_1545delAAC variant results in an in-frame deletion of an Asparagine residue at position 515, which is a residue that is highly conserved across species. However, in the absence of functional studies, the physiological consequence of this variant cannot be precisely determined. Nevertheless, the c.1543_1545delAAC variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). Finally, other in-frame deletions of single amino acid residues in the MYBPC3 gene have also been reported in association with cardiomyopathy (Stenson et al., 2014).
Invitae	RCV000456611	SCV000546447	uncertain significance	Hypertrophic cardiomyopathy	2024-01-16	criteria provided, single submitter	clinical testing	This variant, c.1543_1545del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Asn515del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs730880643, gnomAD 0.004%). This variant has been observed in individuals with clinical features of dilated cardiomyopathy, clinical features of hypertrophic cardiomyopathy, dilated cardiomyopathy, and/or hypertrophic cardiomyopathy (PMID: 21750094, 33892289, 35653365; Invitae). ClinVar contains an entry for this variant (Variation ID: 181070). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV001525551	SCV001735696	uncertain significance	Cardiomyopathy	2023-03-24	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid in exon 17 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 33495597, 33892289) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has been identified in 3/280634 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.
Ambry Genetics	RCV002399573	SCV002706265	uncertain significance	Cardiovascular phenotype	2020-10-07	criteria provided, single submitter	clinical testing	The c.1543_1545delAAC variant (also known as p.N515del) is located in coding exon 17 of the MYBPC3 gene. This variant results from an in-frame AAC deletion at nucleotide positions 1543 to 1545. This results in the in-frame deletion of an asparagine at codon 515. This alteration has been reported in a subject with dilated cardiomyopathy and has been seen in a mitochondrial disorders cohort (Waldmüller S et al, Eur J Heart Failure. 2011 Nov;13:1185-92; Puusepp S et al, Mol Genet Mteb Rep. 2018 Jun;15:80-89).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003493462	SCV004242494	uncertain significance	Left ventricular noncompaction 10	2023-12-29	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM2_SUP,PM4_SUP