ClinVar Miner

Submissions for variant NM_000382.3(ALDH3A2):c.529C>T (p.Arg177Ter) (rs72547561)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255332 SCV000321387 pathogenic not provided 2017-08-30 criteria provided, single submitter clinical testing The R177X mutation in the ALDH3A2 gene has been reported previously in association with Sjögren-Larsson syndrome (SLS) (Carney et al., 2004).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255332 SCV000339070 pathogenic not provided 2016-02-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000316840 SCV000401252 likely pathogenic Sjögren-Larsson syndrome 2017-05-04 criteria provided, single submitter clinical testing The ALDH3A2 c.529C>T (p.Arg177Ter) variant is a stop-gained variant that has been reported in a compound heterozygous state with a second truncating variant in two unrelated individuals with Sjogren-Larsson syndrome (SLS), and in a heterozygous state in the unaffected father of one of the individuals (Carney et al. 2004; Nagappa et al. 2016). Control data are unavailable for the p.Arg177Ter variant, which is reported at a frequency of 0.00042 in the Latino population of the Genome Aggregation Database. FALDH activity in cultured skin fibroblasts from one of the individuals was 4% that of normal fibroblasts (Carney et al. 2004). Based on the evidence from the literature and the potential impact of stop-gained variants, the p.Arg177Ter variant is classified as likely pathogenic for Sjogren-Larsson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000316840 SCV000918412 pathogenic Sjögren-Larsson syndrome 2018-09-03 criteria provided, single submitter clinical testing Variant summary: ALDH3A2 c.529C>T (p.Arg177X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (eg. c.1291_1292delAA (p.Lys431fsX5)). The variant allele was found at a frequency of 5.7e-05 in 246266 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALDH3A2 causing Sjogren-Larsson Syndrome (5.7e-05 vs 0.0018), allowing no conclusion about variant significance. c.529C>T has been reported in the literature in individuals affected with Sjogren-Larsson Syndrome, in one case the patient was reported to have <10% enzyme activity (Carney_2004, Nagappa_2017). Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (3x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000255332 SCV001212449 pathogenic not provided 2020-08-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg177*) in the ALDH3A2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs72547561, ExAC 0.03%). This variant has been observed in individual(s) with Sjögren-Larsson syndrome (PMID: 15241804). ClinVar contains an entry for this variant (Variation ID: 265027). Loss-of-function variants in ALDH3A2 are known to be pathogenic (PMID: 10577908, 10854114). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000316840 SCV000800797 pathogenic Sjögren-Larsson syndrome 2017-12-04 no assertion criteria provided clinical testing
Natera, Inc. RCV000316840 SCV001459270 pathogenic Sjögren-Larsson syndrome 2020-09-16 no assertion criteria provided clinical testing

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