NM_000382.3(ALDH3A2):c.733G>A (p.Asp245Asn) AND not provided

Clinical significance:Pathogenic (Last evaluated: Jul 15, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000255515.4

Allele description [Variation Report for NM_000382.3(ALDH3A2):c.733G>A (p.Asp245Asn)]

NM_000382.3(ALDH3A2):c.733G>A (p.Asp245Asn)

Gene:
ALDH3A2:aldehyde dehydrogenase 3 family member A2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p11.2
Genomic location:
Preferred name:
NM_000382.3(ALDH3A2):c.733G>A (p.Asp245Asn)
HGVS:
  • NC_000017.11:g.19657797G>A
  • NG_007095.2:g.14047G>A
  • NM_000382.3:c.733G>AMANE SELECT
  • NM_001031806.2:c.733G>A
  • NM_001369136.1:c.733G>A
  • NM_001369137.1:c.733G>A
  • NM_001369138.1:c.733G>A
  • NM_001369139.1:c.733G>A
  • NM_001369146.1:c.733G>A
  • NM_001369148.1:c.154G>A
  • NP_000373.1:p.Asp245Asn
  • NP_001026976.1:p.Asp245Asn
  • NP_001356065.1:p.Asp245Asn
  • NP_001356066.1:p.Asp245Asn
  • NP_001356067.1:p.Asp245Asn
  • NP_001356068.1:p.Asp245Asn
  • NP_001356075.1:p.Asp245Asn
  • NP_001356077.1:p.Asp52Asn
  • NC_000017.10:g.19561110G>A
  • NM_000382.2:c.733G>A
  • P51648:p.Asp245Asn
Protein change:
D245N
Links:
UniProtKB: P51648#VAR_002252; dbSNP: rs72547568
NCBI 1000 Genomes Browser:
rs72547568
Molecular consequence:
  • NM_000382.3:c.733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001031806.2:c.733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369136.1:c.733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369137.1:c.733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369138.1:c.733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369139.1:c.733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369146.1:c.733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369148.1:c.154G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000322393GeneDxcriteria provided, single submitter
Pathogenic
(May 31, 2016)
germlineclinical testing

Citation Link,

SCV000949868Invitaecriteria provided, single submitter
Pathogenic
(Jul 15, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjögren-Larsson syndrome.

Willemsen MA, IJlst L, Steijlen PM, Rotteveel JJ, de Jong JG, van Domburg PH, Mayatepek E, Gabreëls FJ, Wanders RJ.

Brain. 2001 Jul;124(Pt 7):1426-37. Review.

PubMed [citation]
PMID:
11408337

Sjögren-Larsson syndrome: novel mutations in the ALDH3A2 gene in a French cohort.

Sarret C, Rigal M, Vaurs-Barrière C, Dorboz I, Eymard-Pierre E, Combes P, Giraud G, Wanders RJ, Afenjar A, Francannet C, Boespflug-Tanguy O.

J Neurol Sci. 2012 Jan 15;312(1-2):123-6. doi: 10.1016/j.jns.2011.08.006. Epub 2011 Aug 26.

PubMed [citation]
PMID:
21872273
See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000322393.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The D245N pathogenic variant in the ALDH3A2 gene has been reported previously in the homozygous state, or as part of a complex allele, in multiple unrelated patients with Sjoegren-Larsson syndrome (SLS) (Rizzo et al., 2009; Willemsen et al., 2001; Sarret et al., 2012). D245N was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, functional studies have shown that the D245N variant almost completely abolishes the enzymatic activity of the protein (Rizzo et al., 1999).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000949868.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces aspartic acid with asparagine at codon 245 of the ALDH3A2 protein (p.Asp245Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs72547568, ExAC 0.001%). This variant has been observed in individual(s) with Sjoegren-Larsson syndrome (PMID: 10577908, 11408337, 21872273). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265459, 438264). This variant has also been described in the literature as part of a complex haplotype in individuals affected with Sjoegren-Larsson syndrome with European heritage (PMID: 29183715, 9829906). In these individuals this variant is described in combination with a complex variant involving three separate sequence changes that occur on the same chromosome (in cis) (c.901 G>C; c.906delT; and c.909 T>G). ClinVar contains an entry for this complex haplotype (Variation ID: 438264). This variant has been reported to affect ALDH3A2 protein function (PMID: 10577908). In summary, this is a rare variant that has been observed as part of a complex European haplotype with a second pathogenic variant. It has been observed in several individuals with Sjögren-Larsson syndrome, and is expected to affect ALDH3A2 protein function. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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