ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.495_501del (p.Pro166fs) (rs1057517429)

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Total submissions: 3
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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 likely pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing The c.495_501delGCCGGCC variant has been reported previously as c.489_495del using alternative nomenclature in association with metachromatic leukodystrophy (Eng et al., 2003). This variant has been identified in three unrelated individuals; all of French Canadian ancestry from the province of New Brunswick, however, additional information was not provided (Eng et al., 2003). The deletion causes a frameshift starting with codon Proline 166, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 32 of the new reading frame, denoted p.Pro166LeufsX32. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.495_501delGCCGGCC variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000410974 SCV001592677 pathogenic Metachromatic leukodystrophy 2020-09-30 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 14517960, 12809638). This variant is also known as c.489_495del, p.Pro163fs or 752_758delGCCGGCC in the literature. ClinVar contains an entry for this variant (Variation ID: 371638). Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). For these reasons, this variant has been classified as Pathogenic.

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