ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.991G>A (p.Glu331Lys)

gnomAD frequency: 0.00002  dbSNP: rs398123419
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671936 SCV000796977 uncertain significance Metachromatic leukodystrophy 2018-01-05 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000671936 SCV000896990 uncertain significance Metachromatic leukodystrophy 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000671936 SCV002186865 pathogenic Metachromatic leukodystrophy 2023-11-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 331 of the ARSA protein (p.Glu331Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809637, 30052522). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 556001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282317 SCV002571864 uncertain significance not specified 2022-08-08 criteria provided, single submitter clinical testing Variant summary: ARSA c.991G>A (p.Glu331Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-06 in 212420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.991G>A was initially reported as G985A (E329R) in the background of a pseudodeficiency allele in a patient, who was one of two affected siblings with late infantile MLD (Metachromatic Leukodystrophy), in presumed compound heterozygosity with another variant C895T (R299W) (also known as c.901C>T, p.Arg301Trp, pathogenic single submitter in ClinVar) (Rafi_2003). Additionally, it has recently been reported as a homozygous genotype in cis with c.1055T>C (p.N352S) in two siblings with MLD who had normal levels of ARSA enzyme activity at the lower limit of the reported reference range (Aslan_2018 cited in Elgun_2013). The variant c.1055T>C reported in Aslan_2018 is presumably c.1055A>G (p.Asn352Ser) supporting an erroneous representation in the published report. Furthermore, c.1055A>G is concordantly classified as benign in the ClinVar database. These data do not allow any conclusion about variant significance. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=1; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002531300 SCV003547111 uncertain significance Inborn genetic diseases 2022-07-24 criteria provided, single submitter clinical testing The c.991G>A (p.E331K) alteration is located in exon 6 (coding exon 6) of the ARSA gene. This alteration results from a G to A substitution at nucleotide position 991, causing the glutamic acid (E) at amino acid position 331 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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