Submissions for variant NM_001791.4(CDC42):c.68A>G (p.Tyr23Cys)

dbSNP: rs797044916

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190749	SCV000244190	pathogenic	Inborn genetic diseases	2021-07-20	criteria provided, single submitter	clinical testing	The c.68A>G (p.Y23C) alteration is located in exon 3 (coding exon 1) of the CDC42 gene. This alteration results from an A to G substitution at nucleotide position 68, causing the tyrosine (Y) at amino acid position 23 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD), the CDC42 c.68A>G alteration was not observed, with coverage at this position. This mutation occurred de novo in two individuals with intellectual deficiency, growth failure, microcephaly, and dysmorphic facial features (Helbig, 2016; Martinelli, 2018; Ambry internal data). Functional analysis demonstrated that the Y23C alteration results in weaker interactions between CDC42 and PAK1, WASP, and FMNL2 as well as a significant decrease in wound healing assay and cell proliferation compared to wild-type (Martinelli, 2018). The p.Y23C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001093410	SCV001250374	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001374925	SCV001572212	pathogenic	Neurodevelopmental disorder	2021-03-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001093410	SCV001758326	pathogenic	not provided	2022-11-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrated a decrease in GAP-stimulated GTP hydrolysis and reduced binding to WASP and FMNL2 proteins, and a wound healing assay showed impaired proliferation of cells (Martinelli et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31601675, 26795593, 29394990, 27513193, 32231661, 30696065, 33936654)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509288	SCV002819575	pathogenic	Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: CDC42 c.68A>G (p.Tyr23Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) 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 251282 control chromosomes. c.68A>G has been reported in the literature in individuals affected with Macrothrombocytopenia-Lymphedema Delay-Facial Dysmorphism-Camptodactyly Syndrome and related disorders (Martinelli_2018, Flynn_2021, Helbig_2016 and Farwell_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Martinelli_2018). The variant showed significantly decreased binding affinity and decreased proliferation. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291420	SCV001479921	likely pathogenic	Abnormal facial shape; Abnormality of blood and blood-forming tissues; Abnormality of the immune system; Postnatal growth retardation; Neurodevelopmental abnormality		no assertion criteria provided	research