VCV000005040.39 - ClinVar

NM_015665.6(AAAS):c.1432C>T (p.Arg478Ter)

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.

(9)

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_015665.6(AAAS):c.1432C>T (p.Arg478Ter)

Variation ID: 5040 Accession: VCV000005040.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.13 12: 53307698 (GRCh38) [ NCBI UCSC ] 12: 53701482 (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	Jul 25, 2015	Oct 20, 2024	Dec 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015665.6:c.1432C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056480.1:p.Arg478Ter	nonsense
NM_001173466.2:c.1333C>T	NP_001166937.1:p.Arg445Ter	nonsense
NC_000012.12:g.53307698G>A
NC_000012.11:g.53701482G>A
NG_016775.1:g.18931C>T

... more HGVS ... less HGVS

Protein change

R478*, R445*

Other names

Canonical SPDI

NC_000012.12:53307697:G:A

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

The Genome Aggregation Database (gnomAD) 0.00007

Links

ClinGen: CA117224 OMIM: 605378.0002 dbSNP: rs121918548 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.
AAAS		-	-	GRCh38 GRCh38 GRCh37	473	494

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.
Glucocorticoid deficiency with achalasia	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 12, 2022	RCV000005343.11
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 4, 2023	RCV000255523.28
Neurodevelopmental disorder	Pathogenic (1)	criteria provided, single submitter	Oct 7, 2021	RCV001778647.2

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glucocorticoid deficiency with achalasia Affected status: yes Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV000996292.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Number of individuals with the variant: 2 Ethnicity/Population group: Arab Geographic origin: Middle East
Pathogenic (Oct 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV002016318.1 First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021
Pathogenic (May 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glucocorticoid deficiency with achalasia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002799259.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Aug 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glucocorticoid deficiency with achalasia Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019721.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 04, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004294182.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 11062474‚ 14646395‚ 29874194‚ 30381913 Comment: This sequence change creates a premature translational stop signal (p.Arg478) in the AAAS gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg478) in the AAAS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the AAAS protein. This variant is present in population databases (rs121918548, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with triple A syndrome (PMID: 11062474, 14646395, 29874194, 30381913). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5040). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 16, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321310.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect due to mislocalization of the ALADIN protein (Krumbholtz et al., 2006); Nonsense variant predicted to result in protein … (more) Published functional studies demonstrate a damaging effect due to mislocalization of the ALADIN protein (Krumbholtz et al., 2006); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 11062474, 12008750, 16609705, 11914417, 14646395, 20499090, 30381913, 29874194, 31980526) (less)
Pathogenic (Apr 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249015.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Mar 26, 2002)	no assertion criteria provided Method: literature only	ACHALASIA-ADDISONIANISM-ALACRIMA SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025521.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 25, 2015	Publications: PubMed (2) PubMed: 11062474‚ 11914417 Comment on evidence: In a family from Portugal with triple-A syndrome (AAAS; 231550), Tullio-Pelet et al. (2000) found a C-to-T transition at nucleotide 1522 in exon 16 of … (more) In a family from Portugal with triple-A syndrome (AAAS; 231550), Tullio-Pelet et al. (2000) found a C-to-T transition at nucleotide 1522 in exon 16 of the AAAS gene, resulting in an arg478-to-ter (R478X) amino acid substitution. Goizet et al. (2002) reported a Portuguese woman who presented at age 33 years with progressive bulbospinal amyotrophy and autonomic dysfunction associated with typical features of the triple-A syndrome, which had been present since birth. She was found to be homozygous for the R478X mutation. (less)
Pathogenic (Jan 29, 2019)	no assertion criteria provided Method: clinical testing	Glucocorticoid deficiency with achalasia Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001132828.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020

Comment:

This sequence change creates a premature translational stop signal (p.Arg478*) in the AAAS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the AAAS protein. This variant is present in population databases (rs121918548, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with triple A syndrome (PMID: 11062474, 14646395, 29874194, 30381913). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5040). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies demonstrate a damaging effect due to mislocalization of the ALADIN protein (Krumbholtz et al., 2006); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 11062474, 12008750, 16609705, 11914417, 14646395, 20499090, 30381913, 29874194, 31980526)

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
Triple A syndrome presenting as complicated hereditary spastic paraplegia.	Leveille E	Molecular genetics & genomic medicine	2018	PMID: 30381913
Clinical heterogeneity and molecular profile of triple A syndrome: a study of seven cases.	Singh K	Journal of pediatric endocrinology & metabolism : JPEM	2018	PMID: 29874194
Three children with triple A syndrome due to a mutation (R478X) in the AAAS gene.	Yuksel B	Hormone research	2004	PMID: 14646395
Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation.	Goizet C	Neurology	2002	PMID: 11914417
Mutant WD-repeat protein in triple-A syndrome.	Tullio-Pelet A	Nature genetics	2000	PMID: 11062474

Text-mined citations for rs121918548 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_015665.6(AAAS):c.1432C>T (p.Arg478Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918548 ...