ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.827C>T (p.Thr276Met) (rs74315472)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169246 SCV000220526 likely pathogenic Metachromatic leukodystrophy 2014-07-20 criteria provided, single submitter literature only
Invitae RCV000169246 SCV000627146 pathogenic Metachromatic leukodystrophy 2020-05-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 276 of the ARSA protein (p.Thr276Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs74315472, ExAC 0.002%). This variant has been reported as homozygous or compound heterozygous in multiple individuals affected with metachromatic leukodystrophy (MLD) with evidence of segregation with disease in one family (PMID: 19815439, 26462614, 8104633, 18786133, Invitae). It has been reported as a prevalent variant in Lebanese or Arabic populations and the majority of individuals homozygous for this variant present the late-infantile form of the disease (PMID: 26462614, 8104633). This variant is also known as T274M in the literature. ClinVar contains an entry for this variant (Variation ID: 3075). Experimental studies have shown that this variant impairs enzyme activity in vitro (PMID: 7825603, 8723680). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169246 SCV000696811 pathogenic Metachromatic leukodystrophy 2017-03-23 criteria provided, single submitter clinical testing Variant summary: The ARSA c.827C>T (p.Thr276Met) variant causes a missense change involving the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is found in the Alkaline-phosphatase-like, core domain (IPR017850). The variant of interest has been observed in a large, broad control population, ExAC, in 1/119904 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSA variant (0.0027951). Multiple studies showed this variant as co-segregating with MLD in families of Lebanese and Italian origins (Harvey_1993, Bertelli_2005). In addition, low arylsulfatase A and sulfatidase activity was observed in peripheral leukocytes and cultured skin fibroblasts in patients carrying the variant. Also, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000169246 SCV000893598 pathogenic Metachromatic leukodystrophy 2018-10-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000991546 SCV001143057 pathogenic not provided 2019-03-18 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/279214 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
Broad Institute Rare Disease Group, Broad Institute RCV000169246 SCV001164368 pathogenic Metachromatic leukodystrophy 2018-12-03 criteria provided, single submitter research The homozygous p.Thr276Met variant (sometimes called p.Thr274Met) in ARSA was identified by our study in one individual with Metachromatic Leukodystrophy. The p.Thr276Met variant in ARSA has been reported in 18 individuals with metachromatic leukodystrophy (most of whom were Arabian or Lebanese), segregated with disease in 4 affected relatives from 2 families (PMID: 19815439, 26462614, 8104633, 7825603), and has been identified in 0.0004068% (1/245818) of chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs74315472). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic and likely pathogenic by Invitae and others in ClinVar (Variation ID: 3075). Invitae also reported the presence of this variant in the compound heterozygous state and in an individual with metachromatic leukodystrophy, slightly increasing the likelihood that the p.Thr276Met variant is pathogenic. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Thr276Met variant may impact protein function by reducing or eliminating catalytic enzyme activity (PMID: 7825603, 8723680). However, these types of assays may not accurately represent biological function. In summary, the p.Thr276Met variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS3, PP1_Moderate, PP3, PM3_Supporting (Richards 2015).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000169246 SCV001367740 pathogenic Metachromatic leukodystrophy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
OMIM RCV000003221 SCV000023379 pathogenic Metachromatic leukodystrophy, severe 1993-01-01 no assertion criteria provided literature only

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