ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3800G>A (p.Arg1267Gln) (rs759698959)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181380 SCV000233681 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. Although the R1267Q variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge, it has been identified in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy/arrhythmia genetic testing at GeneDx. Thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the Exome Aggregation Consortium, indicating it is not a common benign variant. The R1267Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Nevertheless, this substitution occurs at a position where amino acids with properties similar to Arginine are tolerated across species, and Arginine 1267 is tolerated in at least one species. 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 benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000697890 SCV000826523 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-03-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1267 of the DSP protein (p.Arg1267Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs759698959, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199934). 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, 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.

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