Submissions for variant NM_020134.4(DPYSL5):c.139G>A (p.Gly47Arg)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056541	SCV005726120	uncertain significance	not specified	2024-11-20	criteria provided, single submitter	clinical testing	Variant summary: DPYSL5 c.139G>A (p.Gly47Arg) results in a non-conservative amino acid change located in the D-HYD domain (IPR011778) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251466 control chromosomes. c.139G>A has been reported in a family affected with Dandy-Walker malformation (DWM) (originally described in Ritscher_1987). One of the sisters affected with DWM had this variant reported as de novo (Aldinger_2019), however this proband had a sibling affected with severe congenital heart defect that was not genotyped. Given the family history authors suspected gonadal mosaicism for inheritance (Jeanne_2022, Ritscher_1987). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence that this variant affects the normal function of the protein (Jeanne_ 2022). The following publications have been ascertained in the context of this evaluation (PMID: 31474318, 33894126, 3812597). ClinVar contains an entry for this variant (Variation ID: 632587). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM	RCV001542270	SCV001760948	pathogenic	Ritscher-Schinzel syndrome 4	2021-07-22	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV001257985	SCV001434798	uncertain significance	Dandy-Walker syndrome		no assertion criteria provided	research
Dobyns Lab, Seattle Children's Research Institute	RCV000779635	SCV000916312	uncertain significance	Ritscher-Schinzel syndrome 1; Syndrome with a Dandy-Walker malformation as major feature	2019-02-18	no assertion criteria provided	research

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