ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.869G>A (p.Arg290His) (rs199476355)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668693 SCV000793337 likely pathogenic Metachromatic leukodystrophy 2017-08-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000668693 SCV000893597 likely pathogenic Metachromatic leukodystrophy 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000668693 SCV000935212 pathogenic Metachromatic leukodystrophy 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 290 of the ARSA protein (p.Arg290His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199476355, ExAC 0.02%). This variant has been observed in combination with another ARSA variant in several individuals affected with metachromatic leukodystrophy (PMID: 10477432, 12809637, 26462614, 15139291). This variant is also known as R288H in the literature. ClinVar contains an entry for this variant (Variation ID: 68153). Experimental studies have shown that this missense change partially reduces arylsulfatase activity in vitro (PMID: 15139291). This variant disrupts the p.Arg290 amino acid residue in ARSA. Another variant that disrupts this residue has been observed in affected individuals (PMID: 7866401, 26462614, 19815439, 17560502, 16678723), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000668693 SCV000966819 likely pathogenic Metachromatic leukodystrophy 2017-09-05 criteria provided, single submitter clinical testing The p.Arg290His (NM_001085425.1 c.869G>A) (also referred to as p.Arg288His in th e literature) variant in ARSA has been reported in 4 compound heterozygous indiv iduals with metachromatic leukodystrophy (Gort 1999, Rafi 2003, Cesani 2016). Pl ease note that this variant has also been reported in cis with a pseudodeficienc y allele (Gort 1999, Rafi 2003). This variant has been identified in 23/110454 o f European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs199476355). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rece ssive carrier frequency. Computational prediction tools and conservation analysi s suggest that the p.Arg290His variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, t he p.Arg290His variant is likely pathogenic for metachromatic leukodystrophy in an autosomal recessive manner based upon observations in trans with other patho genic variants in affected individuals and low frequency in controls.
UniProtKB/Swiss-Prot RCV000058984 SCV000090505 not provided not provided no assertion provided not provided

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