NM_002860.4(ALDH18A1):c.73A>G (p.Thr25Ala) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 4, 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:: RCV003777575.2

Allele description [Variation Report for NM_002860.4(ALDH18A1):c.73A>G (p.Thr25Ala)]

NM_002860.4(ALDH18A1):c.73A>G (p.Thr25Ala)

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.73A>G (p.Thr25Ala)

Other names:

p.Thr25Ala

HGVS:

NC_000010.11:g.95653305T>C
NG_012258.1:g.8506A>G
NM_001017423.2:c.73A>G
NM_001323412.2:c.-46A>G
NM_001323413.2:c.73A>G
NM_001323414.2:c.73A>G
NM_001323415.2:c.73A>G
NM_001323416.2:c.-46A>G
NM_001323417.2:c.73A>G
NM_001323418.2:c.-46A>G
NM_001323419.2:c.-94A>G
NM_002860.4:c.73A>GMANE SELECT
NP_001017423.1:p.Thr25Ala
NP_001310342.1:p.Thr25Ala
NP_001310343.1:p.Thr25Ala
NP_001310344.1:p.Thr25Ala
NP_001310346.1:p.Thr25Ala
NP_002851.2:p.Thr25Ala
NC_000010.10:g.97413062T>C

Protein change:

T25A

Molecular consequence:

NM_001323412.2:c.-46A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001323416.2:c.-46A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001323418.2:c.-46A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001323419.2:c.-94A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001017423.2:c.73A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323413.2:c.73A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323414.2:c.73A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323415.2:c.73A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323417.2:c.73A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002860.4:c.73A>G - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003524447	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 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

SCV003524447

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 4, 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003524447.2

#	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 threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 25 of the ALDH18A1 protein (p.Thr25Ala). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 2202333). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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: Nov 24, 2024

ClinVar

Relating variation to medicine