Submissions for variant NM_000382.3(ALDH3A2):c.683G>A (p.Arg228His)

gnomAD frequency: 0.00002  dbSNP: rs866392702

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809699	SCV000949865	pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 228 of the ALDH3A2 protein (p.Arg228His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ALDH3A2-related conditions (PMID: 22397046, 29704247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 653859). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg228 amino acid residue in ALDH3A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10577908, 27717089). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001334407	SCV001527249	pathogenic	Sjögren-Larsson syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001334407	SCV004028637	pathogenic	Sjögren-Larsson syndrome	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: ALDH3A2 c.683G>A (p.Arg228His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant is also located close to a splice-site: 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251402 control chromosomes (gnomAD). c.683G>A has been reported in the literature in multiple homozygous individuals affected with Sjogren-Larsson Syndrome (e.g. Yis 2012, Vural_2018), and in two large families the variant segregated with the disease. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different missense affecting the same amino acid (R228C) has been also reported in several patients (see HGMD, and PMID 30372562). The following publications have been ascertained in the context of this evaluation (PMID: 22397046, 29704247). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.