Submissions for variant NM_001347721.2(DYRK1A):c.2220dup (p.Met741fs)

dbSNP: rs2053783768

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001352230	SCV001546767	uncertain significance	DYRK1A-related intellectual disability syndrome	2022-04-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met750Hisfs*13) in the DYRK1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the DYRK1A protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DYRK1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1047506). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant 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.
GeneDx	RCV001655717	SCV001871098	uncertain significance	not provided	2021-06-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation as the last 14 amino acids are replaced with 12 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331127	SCV004039414	uncertain significance	not specified	2023-08-25	criteria provided, single submitter	clinical testing	Variant summary: DYRK1A c.2247dupC (p.Met750HisfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however nonsense mediated decay is not expected. The variant was absent in 251396 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2247dupC in individuals affected with Mental Retardation, Autosomal Dominant 7 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.