ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.495_501del (p.Pro166fs)

dbSNP: rs1057517429
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410974 SCV000487270 pathogenic Metachromatic leukodystrophy 2016-11-04 criteria provided, single submitter clinical testing
GeneDx RCV001008063 SCV001167800 pathogenic not provided 2020-07-31 criteria provided, single submitter clinical testing Reported previously as c.489_495del using alternative nomenclature in association with metachromatic leukodystrophy (Eng et al., 2003); Frameshift 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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12809638, 14517960)
Invitae RCV000410974 SCV001592677 pathogenic Metachromatic leukodystrophy 2023-08-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 371638). This variant is also known as c.489_495del, p.Pro163fs or 752_758delGCCGGCC. This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809638, 14517960). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Pro166Leufs*32) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410974 SCV002556210 pathogenic Metachromatic leukodystrophy 2022-06-28 criteria provided, single submitter clinical testing Variant summary: ARSA c.495_501delGCCGGCC (p.Pro166LeufsX32) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.2e-06 in 243028 control chromosomes (gnomAD). c.495_501delGCCGGCC has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (e.g. Eng_2003, Coulter-Mackie_2003), including one case where it was confirmed to be in trans with a pathogenic variant. These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000410974 SCV002081674 pathogenic Metachromatic leukodystrophy 2020-01-31 no assertion criteria provided clinical testing

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