NM_015665.6(AAAS):c.1144_1147del (p.Ser382fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000255826.10

Allele description [Variation Report for NM_015665.6(AAAS):c.1144_1147del (p.Ser382fs)]

NM_015665.6(AAAS):c.1144_1147del (p.Ser382fs)

Gene:

AAAS:aladin WD repeat nucleoporin [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

12q13.13

Genomic location:

Preferred name:

NM_015665.6(AAAS):c.1144_1147del (p.Ser382fs)

HGVS:

NC_000012.11:g.53702253_53702256del
NC_000012.12:g.53308469CAGA[1]
NG_016775.1:g.18153TCTG[1]
NM_001173466.2:c.1045_1048del
NM_015665.6:c.1144_1147delMANE SELECT
NP_001166937.1:p.Ser349fs
NP_056480.1:p.Ser382fs
NC_000012.11:g.53702253CAGA[1]
NC_000012.11:g.53702253_53702256del
NC_000012.11:g.53702253_53702256delCAGA
NM_015665.5:c.1144_1147delTCTG
p.Ser382ArgfsX33

Protein change:

S349fs

Links:

dbSNP: rs770214071

NCBI 1000 Genomes Browser:

rs770214071

Molecular consequence:

NM_001173466.2:c.1045_1048del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_015665.6:c.1144_1147del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321308	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 10, 2022)	germline	clinical testing	Citation Link,
SCV001581120	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11159947, 12429595, 30069287, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321308

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 10, 2022)

germline

clinical testing

Citation Link,

SCV001581120

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 15, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene.

Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A.

Hum Mol Genet. 2001 Feb 1;10(3):283-90.

PubMed [citation]

PMID:: 11159947

Clinical and genetic characterization of families with triple A (Allgrove) syndrome.

Houlden H, Smith S, De Carvalho M, Blake J, Mathias C, Wood NW, Reilly MM.

Brain. 2002 Dec;125(Pt 12):2681-90.

PubMed [citation]

PMID:: 12429595

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000321308.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Frameshift 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: 21865313, 12429595, 30069287, 31589614, 34258490)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001581120.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 264993). This sequence change creates a premature translational stop signal (p.Ser382Argfs*33) in the AAAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AAAS are known to be pathogenic (PMID: 11159947). This variant is present in population databases (rs770214071, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with triple-A syndrome (PMID: 12429595, 30069287). This variant is also known as 1226-1229delTCTG.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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