NM_002860.4(ALDH18A1):c.1393G>A (p.Glu465Lys) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 14, 2023
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:: RCV003769032.1

Allele description

NM_002860.4(ALDH18A1):c.1393G>A (p.Glu465Lys)

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.1393G>A (p.Glu465Lys)

HGVS:

NC_000010.11:g.95621105C>T
NG_012258.1:g.40706G>A
NM_001017423.2:c.1387G>A
NM_001323412.2:c.1060G>A
NM_001323413.2:c.1393G>A
NM_001323414.2:c.1393G>A
NM_001323415.2:c.1387G>A
NM_001323416.2:c.1060G>A
NM_001323417.2:c.1288G>A
NM_001323418.2:c.1054G>A
NM_001323419.2:c.757G>A
NM_002860.4:c.1393G>AMANE SELECT
NP_001017423.1:p.Glu463Lys
NP_001310341.1:p.Glu354Lys
NP_001310342.1:p.Glu465Lys
NP_001310343.1:p.Glu465Lys
NP_001310344.1:p.Glu463Lys
NP_001310345.1:p.Glu354Lys
NP_001310346.1:p.Glu430Lys
NP_001310347.1:p.Glu352Lys
NP_001310348.1:p.Glu253Lys
NP_002851.2:p.Glu465Lys
NC_000010.10:g.97380862C>T
NC_000010.10:g.97380862C>T
NM_002860.3:c.1393G>A

Protein change:

E253K

Links:

dbSNP: rs757876226

NCBI 1000 Genomes Browser:

rs757876226

Molecular consequence:

NM_001017423.2:c.1387G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323412.2:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323413.2:c.1393G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323414.2:c.1393G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323415.2:c.1387G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323416.2:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323417.2:c.1288G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323418.2:c.1054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323419.2:c.757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002860.4:c.1393G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cutis laxa, autosomal dominant 3 (ADCL3)
Identifiers:: MONDO: MONDO:0014706; MedGen: C4225268; Orphanet: 90348; OMIM: 616603

Name:: Autosomal dominant spastic paraplegia type 9
Identifiers:: MONDO: MONDO:0015091; MedGen: C1832669

Name:: de Barsy syndrome (ARCL3A)
Synonyms:: Corneal clouding cutis laxa mental retardation; Progeroid syndrome of De Barsy; Cutis laxa growth deficiency syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0017569; MedGen: C0268354

Recent activity

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RecName: Full=Pectate lyase 1; AltName: Full=Major pollen allergen Jun a 1; AltN...
RecName: Full=Pectate lyase 1; AltName: Full=Major pollen allergen Jun a 1; AltName: Allergen=Jun a 1; Flags: Precursor
gi|9087152|sp|P81294.1|PLY1_JUNAS

Protein
Autosomal dominant spastic paraplegia type 9
Autosomal dominant spastic paraplegia type 9

MedGen
C1832669[conceptid] (1)
MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003014761	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003014761

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 14, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003014761.2

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 465 of the ALDH18A1 protein (p.Glu465Lys). This variant is present in population databases (rs757876226, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALDH18A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 872769). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH18A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 16, 2024

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