Submissions for variant NM_004415.4(DSP):c.2933T>A (p.Ile978Lys)

gnomAD frequency: 0.00001  dbSNP: rs1060500615

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000470333	SCV000543257	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177371	SCV001341569	uncertain significance	Cardiomyopathy	2023-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with lysine at codon 978 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 one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 3/251460 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	RCV003380568	SCV004088815	uncertain significance	Cardiovascular phenotype	2023-08-21	criteria provided, single submitter	clinical testing	The p.I978K variant (also known as c.2933T>A), located in coding exon 21 of the DSP gene, results from a T to A substitution at nucleotide position 2933. The isoleucine at codon 978 is replaced by lysine, an amino acid with dissimilar properties. This variant co-occurred with an MYH7 variant in an individual from a dilated cardiomyopathy cohort (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). This amino acid position is well 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786305	SCV000925070	uncertain significance	not provided	2016-11-10	no assertion criteria provided	provider interpretation	p.Ile978Lys (c.2933T>A) in the DSP gene (NM_004415.2) The lab classifies this variant as a variant of unknown significance. Given a lack of case data we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been previously reported in the literature. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.942) and mutation taster predicts the variant to be disease causing (0.999). The lysine at codon 978 is conserved across close species, but the UCSC geneome browser reports the T at the position is not well conserved in other species suggesting there may be lack of conservation beyond the eight species reported in the mutation taster database. The nearest missense pathogenic or likely pathogenic entries into clinvar are at codons 895 987 and 1601. The variant resides at the end of the globular 1 domain of the desmoplakin domain which includes the first 1056 amino acids of the protein. Kapplinger et al., 2011 from Ackerman's group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants-similar to the 21% yield in 175 Dutch and unit(s).S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC related genes need to be interpreted with cation. Kapplinger et al. Also report a "hot spot" for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. In total the variant has not been seen in laboratory controls, published controls and individuals from publicly available population datasets. There are three individuals with p.Ile978Lys and two individuals with p.Ile978Val at codon 978 listed in the gnomAD dataset (http://gnomad.broadinstitute.org/). gnomAD currently includes variant calls on ~126,000 individuals of European, African, Latino and Asian descent (as of November 10, 2016). The average coverage at that site in gnomAD is around 50x.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000786305	SCV001928576	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000786305	SCV001959032	uncertain significance	not provided		no assertion criteria provided	clinical testing