ClinVar Miner

Submissions for variant NM_001347721.2(DYRK1A):c.1803CCA[7] (p.His609_His610dup) (rs760576043)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001696973 SCV000582650 likely benign not provided 2019-03-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000493224 SCV000594479 likely benign not specified 2017-08-30 criteria provided, single submitter clinical testing
Invitae RCV000686520 SCV000814041 uncertain significance Mental retardation, autosomal dominant 7 2020-08-25 criteria provided, single submitter clinical testing This variant, c.1839_1844dupCCACCA, results in the insertion of 2 amino acid to the DYRK1A protein (p.His618_His619dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766324725, ExAC 0.02%). This variant has not been reported in the literature in individuals with DYRK1A-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000493224 SCV001448383 likely benign not specified 2020-11-05 criteria provided, single submitter clinical testing Variant summary: DYRK1A c.1839_1844dupCCACCA (p.His618_His619dup) results in an in-frame duplication that is predicted to add two additional histidine amino acid residues to a histidine repeat region (that is consisting of 13 consecutive histidines). The variant allele was found at a frequency of 8e-05 in 250312 control chromosomes, predominantly found in the North-western European subpopulation, with a frequency of 0.00024 (i.e. 10/42006 alleles) in the gnomAD database (v2, exomes dataset). To our knowledge, no occurrence of c.1839_1844dupCCACCA in individuals affected with Mental Retardation, Autosomal Dominant 7 and no experimental evidence demonstrating its impact on protein function have been reported. However recent functional studies elucidating the role of the affected histidine repeat, found that this repeat region is a nuclear speckle-targeting signal, where a repeat length of 6 His residues is sufficient to target a heterologous protein to the nuclear speckles, moreover a positive relationship was detected between the accumulation in nuclear speckles and the length of the His-tract (PMIDs: 12799418, 19266028); therefore the elongation of this histidine repeat region by our variant of interest could be expected to be of no functional impact. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=1) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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