ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.943C>T (p.Pro315Ser) (rs72547571)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Institute Rare Disease Group, Broad Institute 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,; 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 Women's Health, 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 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 315 of the ALDH3A2 protein (p.Pro315Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs72547571, ExAC 0.03%). This variant is a known common cause of Sjögren-Larsson syndrome (SLS) among individuals originating from the northern part of Sweden (PMID: 9254849). This variant has been observed to be homozygous or in combination with another ALDH3A2 variant in unrelated individuals with SLS and to segregate with disease in families (PMID: 11408337, 19124283, 10384396, 9204959). ClinVar contains an entry for this variant (Variation ID: 1640). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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
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

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