Submissions for variant NM_004415.4(DSP):c.1323G>C (p.Lys441Asn)

gnomAD frequency: 0.00001  dbSNP: rs1037212969

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498264	SCV000590294	uncertain significance	not provided	2017-06-07	criteria provided, single submitter	clinical testing	The K441N variant of uncertain significance in the DSP gene has been reported in one individual who also harbored the c.2146-1 G>C pathogenic variant in the PKP2 gene (Abrams et al., 2015), though no segregation data is available to determine of the K441N variant in the DSP gene independently segregated with disease. This variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating it is not a common benign variant. The K441N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000641782	SCV000763431	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002383958	SCV002690461	uncertain significance	Cardiovascular phenotype	2023-07-21	criteria provided, single submitter	clinical testing	The p.K441N variant (also known as c.1323G>C), located in coding exon 11 of the DSP gene, results from a G to C substitution at nucleotide position 1323. The lysine at codon 441 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002481588	SCV002778315	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2021-08-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532148	SCV004363296	uncertain significance	Cardiomyopathy	2022-11-03	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 441 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 been reported in an individual affected with arrhythmogenic cardiomyopathy, who also carried a pathogenic splicing variant in the PKP2 gene that could explain the observed phenotype (PMID: 26099957). This variant has been identified in 5/282688 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.