1-22078546-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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: Genomes: not found (cov: 32)
• Consequence: CDC42 NM_001791.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.67

Genes affected

CDC42 (HGNC:1736): (cell division cycle 42) The protein encoded by this gene is a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression. This protein is highly similar to Saccharomyces cerevisiae Cdc 42, and is able to complement the yeast cdc42-1 mutant. The product of oncogene Dbl was reported to specifically catalyze the dissociation of GDP from this protein. This protein could regulate actin polymerization through its direct binding to Neural Wiskott-Aldrich syndrome protein (N-WASP), which subsequently activates Arp2/3 complex. Alternative splicing of this gene results in multiple transcript variants. Pseudogenes of this gene have been identified on chromosomes 3, 4, 5, 7, 8 and 20. [provided by RefSeq, Apr 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 9) in uniprot entity CDC42_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001791.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-22078545-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 987296.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 1-22078546-A-G is Pathogenic according to our data. Variant chr1-22078546-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-22078546-A-G is described in Lovd as [Pathogenic]. Variant chr1-22078546-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC42	NM_001791.4	c.68A>G	p.Tyr23Cys	missense_variant	2/6	ENST00000656825.1
CDC42	NM_001039802.2	c.68A>G	p.Tyr23Cys	missense_variant	3/7
CDC42	NM_044472.3	c.68A>G	p.Tyr23Cys	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC42	ENST00000656825.1	c.68A>G	p.Tyr23Cys	missense_variant	2/6		NM_001791.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
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) -

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. -

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

- -

Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome Pathogenic:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;.;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.94	D
Polyphen		1.0, 1.0	.;D;D;D;.
Vest4		0.93, 0.93, 0.91
MutPred		0.85		Loss of ubiquitination at K27 (P = 0.0863);Loss of ubiquitination at K27 (P = 0.0863);Loss of ubiquitination at K27 (P = 0.0863);Loss of ubiquitination at K27 (P = 0.0863);Loss of ubiquitination at K27 (P = 0.0863);
MVP		0.93
MPC		4.2
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797044916; hg19: chr1-22405039;