Submissions for variant NM_000382.3(ALDH3A2):c.1270C>T (p.Pro424Ser)

gnomAD frequency: 0.00419  dbSNP: rs61737992

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000259377	SCV000336031	likely benign	not specified	2017-11-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346445	SCV000401261	likely benign	Sjögren-Larsson syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000346445	SCV000744968	likely benign	Sjögren-Larsson syndrome	2016-03-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000676617	SCV001101413	benign	not provided	2025-01-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000676617	SCV001151247	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	ALDH3A2: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000259377	SCV002547996	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing	Variant summary: ALDH3A2 c.1270C>T (p.Pro424Ser) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0043 in 251464 control chromosomes, predominantly at a frequency of 0.0065 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALDH3A2 causing Sjogren-Larsson Syndrome phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (n=2) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000676617	SCV005212353	likely benign	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000346445	SCV000733576	likely benign	Sjögren-Larsson syndrome		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000676617	SCV000802409	likely benign	not provided	2016-02-24	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000346445	SCV001452937	benign	Sjögren-Larsson syndrome	2020-01-04	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930084	SCV004741559	likely benign	ALDH3A2-related disorder	2021-06-04	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).