rs730880264

Variant names:

• chr17-19663333-CCC-GGGCTAAAAGTACTGTTGGGG
• rs730880264
• NM_000382.3:c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_000382.3(ALDH3A2):​c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG​(p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla) variant causes a missense, disruptive inframe insertion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A314A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH3A2 NM_000382.3 missense, disruptive_inframe_insertion, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.83
• Publications: 1 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 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000382.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000382.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-19663333-CCC-GGGCTAAAAGTACTGTTGGGG is Pathogenic according to our data. Variant chr17-19663333-CCC-GGGCTAAAAGTACTGTTGGGG is described in ClinVar as Pathogenic. ClinVar VariationId is 1638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH3A2	NM_000382.3	c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG	p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla	missense_variant, disruptive_inframe_insertion, splice_region_variant		ENST00000176643.11	NP_000373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH3A2	ENST00000176643.11	c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG	p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla	missense_variant, disruptive_inframe_insertion, splice_region_variant		1	NM_000382.3	ENSP00000176643.6

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sjögren-Larsson syndrome Pathogenic:4

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2022

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.941_943delinsGGGCTAAAAGTACTGTTGGGG (p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla) results in an in-frame deletion/insertion that is predicted to delete 2 amino acids and insert 8 amino acids into the encoded protein. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. c.941_943delinsGGGCTAAAAGTACTGTTGGGG has been reported in the literature in individuals affected with Sjogren-Larsson Syndrome or related disorders. These data indicate that the variant may be associated with disease. At least two publications report that FALDH activity in patients carrying this variant is <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Sjogren-Larsson syndrome (MIM#270200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). However, as this is a complex variant it may be misannotated in gnomAD. There are several variants gnomAD v3 which, if combined, may be this variant (2 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated aldehyde dehydrogenase family domain (DECIPHER). (I) 0704 - A missense variant involving one of the residues affected by the variant identified in this case has limited previous evidence for pathogenicity. p.(Pro315Ser) has been reported as pathogenic by multiple clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenic in unrelated individuals. This variant has been classified as pathogenic by a clinical laboratory in ClinVar, and has been observed in four individuals with Sjogren-Larsson syndrome in the literature (PMIDs: 8528251, 34531397, 9250352, 9829906). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. An individual homozygous for this variant was shown to have 8% of mean ALDH3A2 activity and their heterozygous parents had 39% and 47% of mean activity (PMID: 8528251). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases Pathogenic:1

Mar 13, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG (p.A314_P315delinsGAKSTVGA) alteration, located in exon 7 (coding exon 7) of the ALDH3A2 gene, consists of an in-frame deletion of 3 and insertion of 21 nucleotides from position 941 to 943, resulting in the deletion of 2 residues and insertion of 8 residues. The impacted region is critical for protein function (Ambry internal data). This variant was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been identified in the homozygous state and/or in conjunction with other ALDH3A2 variant(s) in individual(s) with features consistent with Sjogren-Larsson syndrome (Carney, 2004; Tanteles, 2015; Sill&eacute;n, 1998; van Eyk, 2021; De Laurenzi, 1996). The deleted amino acid positions are highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Cerebral palsy Pathogenic:1

Jun 10, 2021

Neurogenetics Research Program, University of Adelaide

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

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

Other links and lift over

dbSNP: rs730880264; hg19: chr17-19566646;