ClinVar Miner

Submissions for variant NM_017825.3(ADPRS):c.530C>T (p.Ser177Leu)

dbSNP: rs200626873
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center RCV000721143 SCV002822962 likely pathogenic Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures 2019-10-07 criteria provided, single submitter clinical testing This variant results in the substitution of the highly-conserved serine at position 177 for a leucine. This variant localizes to coding exon 4 of the ADPRHL2 gene (6 coding exons in total; NM_017825.3), and is localized in a critical alpha-helical loop within the ADP-ribosylhydrolase domain (PMID: 30100084). In silico analysis predicts this change to be deleterious to the structure and/or function of the protein (possibly damaging by Polyphen2 and deleterious by SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (1/246,898), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in a homozygous state in two siblings with progressive weakness, seizures and deteriorating speech and motor development from a consanguineous Iranian family. Although functional studies of the variant and studies of patient cells were not performed, it was predicted to result in a loss of function (PMID: 30100084). Given this evidence, this variant is classified as likely pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000721143 SCV004046106 likely pathogenic Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures criteria provided, single submitter clinical testing This variant has been previously reported as a homozygous change in patients with Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome (PMID: 30100084). The c.530C>T (p.Ser177Leu) variant is located in the ADP-ribosyl-glycohydrolase, which is a known hotspot domain for pathogenic variations associated with Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome (PMID: 30100084). The c.530C>T (p.Ser177Leu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/246898) and is absent in the homozygous state, thus it is presumed to be rare. The c.530C>T (p.Ser177Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.530C>T (p.Ser177Leu) variant is classified as Likely Pathogenic.
OMIM RCV000721143 SCV000852026 pathogenic Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures 2018-11-08 no assertion criteria provided literature only

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