Submissions for variant NM_004415.4(DSP):c.3600T>G (p.Asn1200Lys)

gnomAD frequency: 0.00012  dbSNP: rs202049575

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171914	SCV000050914	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000171914	SCV000233539	uncertain significance	not provided	2015-10-05	criteria provided, single submitter	clinical testing	The N1200K variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. The N1200K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the N1200K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Also, this substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000693151	SCV000821007	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001523968	SCV001733714	uncertain significance	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1200 of the DSP 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 not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 20/282354 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	RCV002453593	SCV002615045	uncertain significance	Cardiovascular phenotype	2021-01-13	criteria provided, single submitter	clinical testing	The p.N1200K variant (also known as c.3600T>G), located in coding exon 23 of the DSP gene, results from a T to G substitution at nucleotide position 3600. The asparagine at codon 1200 is replaced by lysine, an amino acid with similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other 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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003387786	SCV004099312	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-10-30	no assertion criteria provided	clinical testing