Submissions for variant NM_004415.4(DSP):c.2622C>G (p.Ile874Met) (rs751067479)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617477	SCV000737910	uncertain significance	Cardiovascular phenotype	2017-02-22	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769222	SCV000900598	uncertain significance	Cardiomyopathy	2016-12-07	criteria provided, single submitter	clinical testing
Color	RCV000769222	SCV000904672	uncertain significance	Cardiomyopathy	2018-10-05	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the plakin domain of the DSP protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 12/276852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx	RCV000181303	SCV000233594	uncertain significance	not provided	2018-07-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSP gene. The I874M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been identified independently of and in conjunction with additional cardiogenetic variants in other individuals referred for cardiac genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The I874M variant has also been observed in 10/126,348 (0.008%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The I874M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae	RCV000535270	SCV000641297	uncertain significance	Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8	2018-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with methionine at codon 874 of the DSP protein (p.Ile874Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs751067479, ExAC 0.007%) but 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.