Submissions for variant NM_000382.3(ALDH3A2):c.943C>T (p.Pro315Ser)

gnomAD frequency: 0.00003  dbSNP: rs72547571

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000255529	SCV000232054	pathogenic	not provided	2014-06-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000255529	SCV000321393	pathogenic	not provided	2016-10-04	criteria provided, single submitter	clinical testing	P315S has been reported previously in association with Sjögren-Larsson syndrome (SLS) and is a common pathogenic variant among individuals of northern European and Swedish ancestry (De Laurenzi et al., 1997). Expression studies demonstrated that this pathogenic variant leads to loss of enzymatic activity (De Laurenzi et al., 1997).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001707	SCV000916434	pathogenic	Sjögren-Larsson syndrome	2018-12-17	criteria provided, single submitter	clinical testing	Variant summary: ALDH3A2 c.943C>T (p.Pro315Ser) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 277112 control chromosomes (gnomAD). The variant, c.943C>T, has been reported in the literature in multiple individuals affected with Sjogren-Larsson Syndrome, in particular in populations of Northern European descent (DeLaurenzi_1997). These data indicate that the variant is very 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% of normal activity (DeLaurenzi_1997). Two clinical diagnostic laboratories have 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000001707	SCV001164350	pathogenic	Sjögren-Larsson syndrome	2018-12-03	criteria provided, single submitter	research	The homozygous p.Pro315Ser variant in ALDH3A2 was identified by our study in one individual with Sjoegren-Larsson syndrome. The p.Pro315Ser variant in ALDH3A2 has been reported in 41 Northern European individuals with Sjoegren-Larsson syndrome, segregated with disease in 2 affected relatives from 1 families (PMID: 9204959, 9254849, 10577908), and has been identified in 0.02132% (27/126636) of European (non-Finnish) chromosomes and 0.003880% (1/25772) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72547571). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The prevalence of the variant in affected Northern European individuals and data from large population studies suggests this is a founder variant with a higher prevalence than the prevalence of the variant in a control population (PMID: 9254849). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported likely pathogenic variant and in an individual with Sjoegren-Larsson syndrome increases the likelihood that the p.Pro315Ser variant is pathogenic (PMID: 10577908; Variation ID: 1643). Functional expression studies with baculovirus and mammalian ovary cells provide some evidence that the p.Pro315Ser variant may impact protein function (PMID: 9204959, 10577908). However, these types of assays may not accurately represent biological function. This variant has also been reported pathogenic in ClinVar (Variation ID: 1640). In summary, the p.Pro315Ser variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS3, PP3, PP1, PS4_Moderate (Richards 2015).
Myriad Genetics, Inc.	RCV000001707	SCV001194171	pathogenic	Sjögren-Larsson syndrome	2019-11-12	criteria provided, single submitter	clinical testing	NM_000382.2(ALDH3A2):c.943C>T(P315S) is classified as pathogenic in the context of Sjogren-Larsson syndrome. Sources cited for classification include the following: PMID 10384396, 9254849, 9204959, 10577908, 9467812 and 11408337. Classification of NM_000382.2(ALDH3A2):c.943C>T(P315S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000255529	SCV001237211	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 315 of the ALDH3A2 protein (p.Pro315Ser). This variant is present in population databases (rs72547571, gnomAD 0.02%). This missense change has been observed in individuals with Sjögren-Larsson syndrome (SLS) (PMID: 9254849). It is commonly reported in individuals of northern Sweden ancestry (PMID: 9204959, 9254849, 10384396, 11408337, 19124283). ClinVar contains an entry for this variant (Variation ID: 1640). 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. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255529	SCV001446918	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000001707	SCV002810359	likely pathogenic	Sjögren-Larsson syndrome	2022-05-09	criteria provided, single submitter	clinical testing
OMIM	RCV000001707	SCV000021863	pathogenic	Sjögren-Larsson syndrome	1999-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000001707	SCV001459273	pathogenic	Sjögren-Larsson syndrome	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255529	SCV001740135	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000255529	SCV001808642	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255529	SCV001959060	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255529	SCV001973886	pathogenic	not provided		no assertion criteria provided	clinical testing