Submissions for variant NM_000487.6(ARSA):c.937C>T (p.Arg313Ter)

dbSNP: rs551472773

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501028	SCV000593421	pathogenic	Metachromatic leukodystrophy	2016-11-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000760416	SCV000890294	pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24001781, 12809637, 30674982)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000501028	SCV001221514	pathogenic	Metachromatic leukodystrophy	2024-07-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg313*) 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). This variant is present in population databases (rs551472773, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809637). This variant is also known as p.Arg311*. ClinVar contains an entry for this variant (Variation ID: 434394). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501028	SCV001361599	pathogenic	Metachromatic leukodystrophy	2019-11-11	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.937C>T (p.Arg313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 242628 control chromosomes (gnomAD). c.937C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Metachromatic Leukodystrophy (Rafi_2003, Luzi_2013). These data indicate that the variant is likely to be associated with disease. These publications also reported decreased enzyme activity and elevated urinary sulfatide excretion in the patients carrying the variant (Rafi_2003, Luzi_2013). Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000501028	SCV001369703	pathogenic	Metachromatic leukodystrophy	2018-10-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000501028	SCV001984758	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000501028	SCV002016558	pathogenic	Metachromatic leukodystrophy	2021-09-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000760416	SCV002585942	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000501028	SCV001132333	likely pathogenic	Metachromatic leukodystrophy	2014-01-02	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000501028	SCV002081648	pathogenic	Metachromatic leukodystrophy	2020-08-05	no assertion criteria provided	clinical testing