ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.641C>T (p.Ala214Val) (rs74315467)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723836 SCV000228887 pathogenic not provided 2014-06-13 criteria provided, single submitter clinical testing
Counsyl RCV000003216 SCV000486818 pathogenic Metachromatic leukodystrophy 2016-08-18 criteria provided, single submitter clinical testing
Invitae RCV000003216 SCV001235946 pathogenic Metachromatic leukodystrophy 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 214 of the ARSA protein (p.Ala214Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs74315467, ExAC 0.005%). This variant has been observed to be homozygous or in combination with another ARSA variant in individuals affected with metachromatic leukodystrophy (PMID: 7906588, 9090526, 9192271, 14517960, 26462614). This variant is also known as p.Ala212Val in the literature. ClinVar contains an entry for this variant (Variation ID: 3070). This variant has been reported to affect ARSA protein function (PMID: 9192271). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003216 SCV001360435 pathogenic Metachromatic leukodystrophy 2019-09-07 criteria provided, single submitter clinical testing Variant summary: ARSA c.641C>T (p.Ala214Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250702 control chromosomes. c.641C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Barth_1993, Gort_1999, Eng_2003, Luzi_2013, Cesani_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000003216 SCV000023374 pathogenic Metachromatic leukodystrophy 1993-12-01 no assertion criteria provided literature only
GeneReviews RCV000003216 SCV000040696 pathologic Metachromatic leukodystrophy 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000003216 SCV001462385 pathogenic Metachromatic leukodystrophy 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000723836 SCV001744911 pathogenic not provided no assertion criteria provided clinical testing

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