ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2933T>A (p.Ile978Lys) (rs1060500615)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470333 SCV000543257 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-07-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with lysine at codon 978 of the DSP protein (p.Ile978Lys). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSP-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
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 ( 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.

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