Submissions for variant NM_016277.5(RAB23):c.434T>A (p.Leu145Ter)

gnomAD frequency: 0.00037  dbSNP: rs121908171

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000407501	SCV000329720	pathogenic	not provided	2022-09-08	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 23599695, 21412941, 24458945, 30487145, 25168863, 20358613, 31980526, 31589614, 17503333)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791402	SCV000637231	pathogenic	Carpenter syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu145*) in the RAB23 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAB23 are known to be pathogenic (PMID: 17503333, 21412941). This variant is present in population databases (rs121908171, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with Carpenter syndrome (PMID: 17503333, 21412941, 24458945). ClinVar contains an entry for this variant (Variation ID: 4591). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000622686	SCV000742468	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000004853	SCV000894388	pathogenic	RAB23-related Carpenter syndrome	2021-12-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004853	SCV001520199	pathogenic	RAB23-related Carpenter syndrome	2020-11-06	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000004853	SCV002019591	pathogenic	RAB23-related Carpenter syndrome	2022-11-23	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000004853	SCV002761661	pathogenic	RAB23-related Carpenter syndrome	2022-03-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000004853	SCV005086764	pathogenic	RAB23-related Carpenter syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Carpenter syndrome (MIM#201000). (I) 0115 - Variants in this gene are known to have variable expressivity. Main features are craniosynostosis, obesity, polydactyly, and soft-tissue syndactylyeatures; additional features are variable (PMID: 17503333). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 125 heterozygotes, 0 homozygotes). (SP) 0702 - Other variants predicted to cause NMD comparable to the one identified in this case have strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been regarded as pathogenic by multiple clinical laboratories in ClinVar and detected in many individuals with Carpenter syndrome, both homozygous and compound heterozygous (PMID: 17503333). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000004853	SCV000025029	pathogenic	RAB23-related Carpenter syndrome	2007-06-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000004853	SCV001453295	pathogenic	RAB23-related Carpenter syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415654	SCV004108343	pathogenic	RAB23-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The RAB23 c.434T>A variant is predicted to result in premature protein termination (p.Leu145*). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with Carpenter syndrome (Jenkins et al. 2007. PubMed ID: 17503333; Jenkins et al. 2011. PubMed ID: 21412941; Salem et al. 2013. PubMed ID: 23599695). This variant is reported in 0.057% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in RAB23 are expected to be pathogenic. This variant is interpreted as pathogenic.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000004853	SCV005367960	pathogenic	RAB23-related Carpenter syndrome	2024-07-09	no assertion criteria provided	clinical testing