ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.474C>A (p.Cys158Ter)

gnomAD frequency: 0.00004  dbSNP: rs768028181
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254939 SCV000322395 pathogenic not provided 2024-03-23 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as p.C156X; This variant is associated with the following publications: (PMID: 36939041, 24001781, 26462614, 37480112)
Labcorp Genetics (formerly Invitae), Labcorp RCV000984244 SCV001224437 pathogenic Metachromatic leukodystrophy 2024-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys158*) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is present in population databases (rs768028181, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with metachromatic leukodystrophy (PMID: 24001781). This variant is also known as 468C>A, p.C156X. ClinVar contains an entry for this variant (Variation ID: 265461). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000254939 SCV002525842 pathogenic not provided 2021-08-25 criteria provided, single submitter clinical testing PM2, PVS1
Fulgent Genetics, Fulgent Genetics RCV000984244 SCV002791010 pathogenic Metachromatic leukodystrophy 2021-08-30 criteria provided, single submitter clinical testing
Counsyl RCV000984244 SCV001132337 likely pathogenic Metachromatic leukodystrophy 2015-07-17 no assertion criteria provided clinical testing
Natera, Inc. RCV000984244 SCV001462390 pathogenic Metachromatic leukodystrophy 2020-09-16 no assertion criteria provided clinical testing
Gelb Laboratory, University of Washington RCV000984244 SCV005046732 not provided Metachromatic leukodystrophy no assertion provided in vitro
PreventionGenetics, part of Exact Sciences RCV004755833 SCV005362055 pathogenic ARSA-related disorder 2024-07-25 no assertion criteria provided clinical testing The ARSA c.474C>A variant is predicted to result in premature protein termination (p.Cys158*). This variant has been reported in the homozygous and compound heterozygous states in patients with autosomal recessive metachromatic leukodystrophy (alternate nomenclature p.Cys156*; Luzi et al. 2013. PubMed ID: 24001781). This variant was also reported in the homozygous state in an individual with delayed speech and language development, developmental regression, spasticity, dystonia, and hypertonia (Tables S1 and S2, Meng et al. 2023. PubMed ID: 36939041). Other early termination changes have been reported as causative both up and downstream; and this variant has been consistently classified as pathogenic in ClinVar. This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ARSA are expected to be pathogenic. This variant is interpreted as pathogenic.

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