Submissions for variant NM_000487.6(ARSA):c.243C>T (p.Gly81=)

gnomAD frequency: 0.02425  dbSNP: rs6151410

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000262492	SCV000331612	benign	not specified	2016-01-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000276455	SCV000439442	benign	Metachromatic leukodystrophy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000276455	SCV000627140	benign	Metachromatic leukodystrophy	2024-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000276455	SCV000677129	benign	Metachromatic leukodystrophy	2017-06-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000262492	SCV001360434	benign	not specified	2019-04-01	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.243C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant alterations at the canonical splice site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0076 in 259806 control chromosomes, predominantly at a frequency of 0.079 within the African subpopulation in the gnomAD database, including 65 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in ARSA causing Metachromatic Leukodystrophy phenotype (0.0028), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.243C>T in individuals affected with Metachromatic Leukodystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (X4) /likely benign (X1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000675753	SCV001942675	benign	not provided	2018-07-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000675753	SCV000801473	benign	not provided	2017-05-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000276455	SCV001452359	benign	Metachromatic leukodystrophy	2020-09-16	no assertion criteria provided	clinical testing