VCV000004591.26 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 4591 Accession: VCV000004591.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.1 6: 57194817 (GRCh38) [ NCBI UCSC ] 6: 57059615 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Oct 13, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016277.5:c.434T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057361.3:p.Leu145Ter	nonsense
NM_001278666.2:c.434T>A	NP_001265595.1:p.Leu145Ter	nonsense
NM_001278667.2:c.434T>A	NP_001265596.1:p.Leu145Ter	nonsense
NM_001278668.2:c.434T>A	NP_001265597.1:p.Leu145Ter	nonsense
NM_183227.3:c.434T>A	NP_899050.1:p.Leu145Ter	nonsense
NC_000006.12:g.57194817A>T
NC_000006.11:g.57059615A>T
NG_012170.1:g.32464T>A

... more HGVS ... less HGVS

Protein change

L145*

Other names

Canonical SPDI

NC_000006.12:57194816:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00040 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00028

Exome Aggregation Consortium (ExAC) 0.00029

Trans-Omics for Precision Medicine (TOPMed) 0.00034

The Genome Aggregation Database (gnomAD) 0.00037

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

Links

ClinGen: CA116937 OMIM: 606144.0001 dbSNP: rs121908171 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RAB23		-	-	GRCh38 GRCh37	247	295

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
RAB23-related Carpenter syndrome	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV000004853.17
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 8, 2022	RCV000407501.5
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Sep 7, 2014	RCV000622686.2
Carpenter syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV000791402.7
RAB23-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 18, 2024	RCV003415654.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RAB23-related Carpenter syndrome Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520199.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Mar 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RAB23-related Carpenter syndrome Affected status: unknown Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761661.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Dec 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RAB23-related Carpenter syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894388.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Sep 08, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329720.9 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Nov 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RAB23-related Carpenter syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019591.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RAB23-related Carpenter syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086764.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 17503333 Comment: 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 … (more) 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 (less)
Pathogenic (Sep 07, 2014)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000742468.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (3) PubMed: 21412941‚ 17503333‚ 24458945 Number of individuals with the variant: 1 Clinical Features: Congenital omphalocele (present) , Craniosynostosis (present) , Clubfoot (present) , Atrial septal defect (present) , Ventricular septal defect (present) , Arthrogryposis multiplex congenita (present) , … (more) Congenital omphalocele (present) , Craniosynostosis (present) , Clubfoot (present) , Atrial septal defect (present) , Ventricular septal defect (present) , Arthrogryposis multiplex congenita (present) , Premature birth (present) , Respiratory distress (present) , Microcephaly (present) , Cloverleaf skull (present) , Ridged cranial sutures (present) , Midface retrusion (present) , Shallow orbits (present) , Proptosis (present) , Low-set, posteriorly rotated ears (present) , Overfolded helix (present) , Stahl ear (present) , Broad thumb (present) , Sacral dimple (present) , Hypertonia (present) , Abnormality of eye movement (present) , Abnormality of brain morphology (present) , Bilateral postaxial polydactyly (present) (less) Sex: female Ethnicity/Population group: Caucasian/African American
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Carpenter syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000637231.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 28492532‚ 17503333‚ 21412941‚ 24458945 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 01, 2007)	no assertion criteria provided Method: literature only	CARPENTER SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025029.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017	Publications: PubMed (1) PubMed: 17503333 Comment on evidence: In 10 probands with Carpenter syndrome (CRPT1; 201000), including 3 each from the Netherlands and the United Kingdom, 2 from Brazil, and 1 each from … (more) In 10 probands with Carpenter syndrome (CRPT1; 201000), including 3 each from the Netherlands and the United Kingdom, 2 from Brazil, and 1 each from the United States and Denmark, Jenkins et al. (2007) found apparent homozygosity for a 434T-A transversion in the RAB23 gene, resulting in a leu145-to-ter (L145X) substitution. A haplotype common to all of these cases was found and shown to contain only 8 genes in addition to RAB23. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Acrocephalopolysyndactyly type II Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453295.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Jun 18, 2024)	no assertion criteria provided Method: clinical testing	RAB23-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004108343.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Jul 09, 2024)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	RAB23-related Carpenter syndrome Affected status: yes Allele origin: maternal	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV005367960.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024
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Comment:

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)

Comment:

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

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Prenatal diagnosis of Carpenter syndrome: looking beyond craniosynostosis and polysyndactyly.	Victorine AS	American journal of medical genetics. Part A	2014	PMID: 24458945
Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay.	Jenkins D	Human mutation	2011	PMID: 21412941
RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.	Jenkins D	American journal of human genetics	2007	PMID: 17503333

Text-mined citations for rs121908171 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908171 ...