Submissions for variant NM_000487.6(ARSA):c.302del (p.Gly101fs)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483135	SCV000574253	pathogenic	not provided	2017-03-16	criteria provided, single submitter	clinical testing	The c.302delG variant in the ARSA gene has been previously reported in an individual with lateinfantile metachromatic leukodystrophy. This individual was also found to be heterozygous foranother variant in the ARSA gene (Chen et al., 2016). The deletion causes a frameshift starting withcodon Glycine 101, changes this amino acid to an Alanine residue and creates a premature Stop codonat position 7 of the new reading frame, denoted p.G101AfsX7. This variant is predicted to cause lossof normal protein function either through protein truncation or nonsense-mediated mRNA decay. Thec.302delG variant is not observed at a significant frequency in large population cohorts (Lek et al.,2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret thisvariant as pathogenic.
Eurofins Ntd Llc (ga)	RCV000483135	SCV000704696	pathogenic	not provided	2017-01-06	criteria provided, single submitter	clinical testing
Invitae	RCV003607294	SCV004539156	pathogenic	Metachromatic leukodystrophy	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly101Alafs*7) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). 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 variant has not been reported in the literature in individuals affected with ARSA-related conditions. ClinVar contains an entry for this variant (Variation ID: 424445). For these reasons, this variant has been classified as Pathogenic.

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