NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln) AND ALDH18A1 deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 17, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001095737.12

Allele description [Variation Report for NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)]

NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

Gene:

ALDH18A1:aldehyde dehydrogenase 18 family member A1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q24.1

Genomic location:

Preferred name:

NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

HGVS:

NC_000010.11:g.95633012C>T
NG_012258.1:g.28799G>A
NM_001017423.2:c.749G>A
NM_001323412.2:c.422G>A
NM_001323413.2:c.755G>A
NM_001323414.2:c.755G>A
NM_001323415.2:c.749G>A
NM_001323416.2:c.422G>A
NM_001323417.2:c.650G>A
NM_001323418.2:c.416G>A
NM_001323419.2:c.119G>A
NM_002860.4:c.755G>AMANE SELECT
NP_001017423.1:p.Arg250Gln
NP_001310341.1:p.Arg141Gln
NP_001310342.1:p.Arg252Gln
NP_001310343.1:p.Arg252Gln
NP_001310344.1:p.Arg250Gln
NP_001310345.1:p.Arg141Gln
NP_001310346.1:p.Arg217Gln
NP_001310347.1:p.Arg139Gln
NP_001310348.1:p.Arg40Gln
NP_002851.2:p.Arg252Gln
NC_000010.10:g.97392769C>T
NM_002860.3:c.755G>A
P54886:p.Arg252Gln
p.R252Q

Protein change:

R139Q; ARG252GLN

Links:

UniProtKB: P54886#VAR_075891; OMIM: 138250.0007; dbSNP: rs864321670

NCBI 1000 Genomes Browser:

rs864321670

Molecular consequence:

NM_001017423.2:c.749G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323412.2:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323413.2:c.755G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323414.2:c.755G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323415.2:c.749G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323416.2:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323417.2:c.650G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323418.2:c.416G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323419.2:c.119G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002860.4:c.755G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: ALDH18A1 deficiency
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001251578	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Feb 17, 2020)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26026163, 26297558 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001251578

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Feb 17, 2020)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.

Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A, Tao F, Konop J, Stoll M, Charles P, Jacoupy M, Matusiak R, Alonso I, Tallaksen C, Mairey M, Kennerson M, Gaussen M, Schule R, Janin M, Morice-Picard F, Durand CM, Depienne C, et al.

Brain. 2015 Aug;138(Pt 8):2191-205. doi: 10.1093/brain/awv143. Epub 2015 May 29.

PubMed [citation]

PMID:: 26026163
PMCID:: PMC4553756

ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism.

Panza E, Escamilla-Honrubia JM, Marco-Marín C, Gougeard N, De Michele G, Morra VB, Liguori R, Salviati L, Donati MA, Cusano R, Pippucci T, Ravazzolo R, Németh AH, Smithson S, Davies S, Hurst JA, Bordo D, Rubio V, Seri M.

Brain. 2016 Jan;139(Pt 1):e3. doi: 10.1093/brain/awv247. Epub 2015 Aug 21. No abstract available.

PubMed [citation]

PMID:: 26297558

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001251578.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The ALDH18A1 c.755G>A (p.Arg252Gln) variant is a missense variant and has been reported in a heterozygous state in at least three unrelated affected individuals presenting with moderate to severe pyramidal signs, pes cavus, cataracts, gastro-oesophageal reflux, chronic cellulitis, and cortical atrophy (Panza et al. 2006; Coutelier et al. 2015). Segregation of the p.Arg252Gln variant with disease was observed in one family in seven affected members over three generations and was absent in all unaffected members (Panza et al. 2016). Functional studies with recombinant p.Arg252Gln variant protein demonstrated that the enzyme activity was reduced compared to wild type (Panza et al. 2016). In addition, the p.Arg252 residue lies in the glutamate-5-kinase domain and is predicted by modelling to lie within the active site (Panza et al. 2006; Coutelier et al. 2015). The p.Arg252Gln variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of ACMG criteria, the p.Arg252Gln variant is classified as pathogenic for ALDH18A1 deficiency.

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

Last Updated: Oct 13, 2024

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