Submissions for variant NM_000487.6(ARSA):c.251C>T (p.Pro84Leu)

gnomAD frequency: 0.00002  dbSNP: rs6151411

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672436	SCV000797541	uncertain significance	Metachromatic leukodystrophy	2018-02-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672436	SCV000947341	pathogenic	Metachromatic leukodystrophy	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the ARSA protein (p.Pro84Leu). This variant is present in population databases (rs6151411, gnomAD 0.004%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18786133, 28762252, 31694723). ClinVar contains an entry for this variant (Variation ID: 556430). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. This variant disrupts the p.Pro84 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 30057904), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000672436	SCV002021437	likely pathogenic	Metachromatic leukodystrophy	2021-01-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672436	SCV002548049	pathogenic	Metachromatic leukodystrophy	2022-05-12	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.251C>T (p.Pro84Leu) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 229438 control chromosomes (gnomAD). c.251C>T has been reported in the literature in multiple compound heterozygous individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, van Rappard_2016, Bohringer_2017, Hettiarachchi_2019, Beeerepoot_2020). 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. Four ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000672436	SCV005656825	likely pathogenic	Metachromatic leukodystrophy	2024-04-25	criteria provided, single submitter	clinical testing
GeneDx	RCV005251164	SCV005902873	pathogenic	not provided	2024-09-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: severely decreased arylsulfatase A enzyme activity (PMID: 37480112); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.245 C>T; p.P82L; This variant is associated with the following publications: (PMID: 27261095, 33855715, 37212343, 31967741, 37480112, 31694723, 7581401, 28762252, 18786133, 32632536)
Gelb Laboratory, University of Washington	RCV000672436	SCV005046668	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro