chr1-22078546-A-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001791.4(CDC42):c.68A>G(p.Tyr23Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y23N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001791.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDC42 | NM_001791.4 | c.68A>G | p.Tyr23Cys | missense_variant | 2/6 | ENST00000656825.1 | NP_001782.1 | |
CDC42 | NM_001039802.2 | c.68A>G | p.Tyr23Cys | missense_variant | 3/7 | NP_001034891.1 | ||
CDC42 | NM_044472.3 | c.68A>G | p.Tyr23Cys | missense_variant | 2/6 | NP_426359.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDC42 | ENST00000656825.1 | c.68A>G | p.Tyr23Cys | missense_variant | 2/6 | NM_001791.4 | ENSP00000499457 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2019 | - - |
Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2022 | 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. - |
Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
Abnormal facial shape;C0850715:Abnormality of blood and blood-forming tissues;C1859778:Postnatal growth retardation;C4021753:Abnormality of the immune system;C4022737:Neurodevelopmental abnormality Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 20, 2021 | 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. - |
CDC42-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 06, 2024 | The CDC42 c.68A>G variant is predicted to result in the amino acid substitution p.Tyr23Cys. This variant has been reported de novo in multiple affected individuals in the literature, and functional studies support its pathogenicity (Helbig et al. 2016. PubMed ID: 26795593; Martinelli et al. 2018. PubMed ID: 29394990). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Mar 11, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at