NM_000382.3(ALDH3A2):c.1297_1298del (p.Glu433fs) AND Sjögren-Larsson syndrome

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jul 17, 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:: RCV000001708.12

Allele description [Variation Report for NM_000382.3(ALDH3A2):c.1297_1298del (p.Glu433fs)]

NM_000382.3(ALDH3A2):c.1297_1298del (p.Glu433fs)

Gene:

ALDH3A2:aldehyde dehydrogenase 3 family member A2 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_000382.3(ALDH3A2):c.1297_1298del (p.Glu433fs)

HGVS:

NC_000017.11:g.19671806GA[2]
NG_007095.2:g.28056GA[2]
NM_000382.3:c.1297_1298delMANE SELECT
NM_001031806.2:c.1297_1298del
NM_001369136.1:c.1297_1298del
NM_001369137.2:c.1297_1298del
NM_001369138.2:c.1297_1298del
NM_001369139.1:c.1297_1298del
NM_001369146.2:c.1208-3753AG[2]
NM_001369148.2:c.718_719del
NP_000373.1:p.Glu433fs
NP_001026976.1:p.Glu433fs
NP_001356065.1:p.Glu433fs
NP_001356066.1:p.Glu433fs
NP_001356067.1:p.Glu433fs
NP_001356068.1:p.Glu433fs
NP_001356077.1:p.Glu240fs
NC_000017.10:g.19575118_19575119del
NC_000017.10:g.19575119GA[2]
NM_000382.2:c.1297_1298del
NM_000382.2:c.1297_1298delGA
NM_000382.3:c.1297_1298delGAMANE SELECT

Protein change:

E240fs

Links:

OMIM: 609523.0006; dbSNP: rs387906256

NCBI 1000 Genomes Browser:

rs387906256

Molecular consequence:

NM_000382.3:c.1297_1298del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001031806.2:c.1297_1298del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369136.1:c.1297_1298del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369137.2:c.1297_1298del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369138.2:c.1297_1298del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369139.1:c.1297_1298del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369148.2:c.718_719del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369146.2:c.1208-3753AG[2] - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Sjögren-Larsson syndrome (SLS)
Synonyms:: FATTY ALCOHOL:NAD+ OXIDOREDUCTASE DEFICIENCY; Fatty aldehyde dehydrogenase deficiency; FADH deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010031; MedGen: C0037231; Orphanet: 816; OMIM: 270200

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F0F1 ATP synthase subunit delta [Sulfuricella denitrificans]
F0F1 ATP synthase subunit delta [Sulfuricella denitrificans]
gi|496498679|ref|WP_009207215.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021864	OMIM	no assertion criteria provided	Pathogenic (May 1, 1999)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9250352, 10384396
SCV000916433	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 11, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20049467, 16837225 Citation Link,
SCV000986929	GenomeConnect, ClinGen	no classification provided	not provided	paternal	phenotyping only
SCV001463379	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002806279	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004041276	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	paternal	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

Mutations associated with Sjögren-Larsson syndrome.

Tsukamoto N, Chang C, Yoshida A.

Ann Hum Genet. 1997 May;61(Pt 3):235-42.

PubMed [citation]

PMID:: 9250352

Molecular basis of Sjögren-Larsson syndrome: frequency of the 1297-1298 del GA and 943C-->T mutation in 29 patients.

Ijlst L, Oostheim W, van Werkhoven M, Willemsen MA, Wanders RJ.

J Inherit Metab Dis. 1999 May;22(3):319-21. No abstract available.

PubMed [citation]

PMID:: 10384396

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000021864.3

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

Description

In a patient with Sjogren-Larsson syndrome (SLS; 270200), Tsukamoto et al. (1997) found a 2-bp deletion (1297_1298delGA) of the ALDH10 gene, with consequent premature chain termination at protein position 434.

In a study of 29 SLS patients with biochemically defined FALDH deficiency in the Netherlands, IJlst et al. (1999) found an allele frequency of 10/58 (17.2%) for the 1297-1298delGA allele.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916433.1

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

Description

Variant summary: ALDH3A2 c.1297_1298delGA (p.Glu433ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.3e-05 in 277238 control chromosomes (gnomAD). c.1297_1298delGA has been reported in the literature in multiple individuals affected with Sjogren-Larsson Syndrome (Gloerich_2006, Rizzo_2010) and patients were found to have significantly reduced FADH activity (<10%; Gloerich_2006). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

From GenomeConnect, ClinGen, SCV000986929.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpretted as pathogenic and reported on 07/26/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

From Natera, Inc., SCV001463379.1

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

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002806279.1

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

#	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

From Baylor Genetics, SCV004041276.1

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

#	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: Sep 29, 2024

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