Submissions for variant NM_004415.4(DSP):c.1136T>C (p.Phe379Ser)

gnomAD frequency: 0.00001  dbSNP: rs1064795084

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479009	SCV000570539	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSP gene. The F379S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The F379S 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. The F379S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is conserved only in mammals. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Color Diagnostics, LLC DBA Color Health	RCV001191586	SCV001359456	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with serine at codon 379 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.
Invitae	RCV001851206	SCV002213722	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2021-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 379 of the DSP protein (p.Phe379Ser). This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 421357). This variant has not been reported in the literature in individuals affected with DSP-related conditions.
Ambry Genetics	RCV002446931	SCV002611681	uncertain significance	Cardiovascular phenotype	2020-03-20	criteria provided, single submitter	clinical testing	The p.F379S variant (also known as c.1136T>C), located in coding exon 9 of the DSP gene, results from a T to C substitution at nucleotide position 1136. The phenylalanine at codon 379 is replaced by serine, an amino acid with highly dissimilar properties. 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.
Fulgent Genetics, Fulgent Genetics	RCV002489162	SCV002784256	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	2021-08-27	criteria provided, single submitter	clinical testing