rs786204759

Variant names:

• chr17-19661229-GCT-CC
• rs786204759
• NM_000382.3:c.901_903delGCTinsCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000382.3(ALDH3A2):​c.901_903delGCTinsCC​(p.Ala301ProfsTer13) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A301P) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH3A2 NM_000382.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.91
• Publications: 0 publications found

Genes affected

ALDH3A2 (HGNC:403): (aldehyde dehydrogenase 3 family member A2) Aldehyde dehydrogenase isozymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This gene product catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acid. Mutations in the gene cause Sjogren-Larsson syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ALDH3A2 Gene-Disease associations (from GenCC):

• Sjogren-Larsson syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-19661229-GCT-CC is Pathogenic according to our data. Variant chr17-19661229-GCT-CC is described in ClinVar as Pathogenic. ClinVar VariationId is 189187.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000382.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH3A2	NM_000382.3	MANE Select	c.901_903delGCTinsCC	p.Ala301ProfsTer13	frameshift missense	Exon 6 of 10	NP_000373.1
	ALDH3A2	NM_001031806.2		c.901_903delGCTinsCC	p.Ala301ProfsTer13	frameshift missense	Exon 6 of 11	NP_001026976.1
	ALDH3A2	NM_001369136.1		c.901_903delGCTinsCC	p.Ala301ProfsTer13	frameshift missense	Exon 7 of 12	NP_001356065.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH3A2	ENST00000176643.11	TSL:1 MANE Select	c.901_903delGCTinsCC	p.Ala301ProfsTer13	frameshift missense	Exon 6 of 10	ENSP00000176643.6
	ALDH3A2	ENST00000339618.8	TSL:1	c.901_903delGCTinsCC	p.Ala301ProfsTer13	frameshift missense	Exon 6 of 11	ENSP00000345774.4
	ALDH3A2	ENST00000476965.5	TSL:1	n.651_653delGCTinsCC		non_coding_transcript_exon	Exon 3 of 7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Sjögren-Larsson syndrome Pathogenic:2

Apr 26, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALDH3A2 c.901_903delinsCC (p.Ala301ProfsX13) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 282830 control chromosomes. c.901_903delinsCC has been reported in the literature with a legacy nomenclature of c.901G>C and c.906delT in individuals affected with Sjogren-Larsson Syndrome (example, Sillen_1998, Keller_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal fatty aldehyde dehydrogenase enzyme activity in patient fibroblasts (example, Keller_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Feb 19, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786204759; hg19: chr17-19564542;