Submissions for variant NM_000487.6(ARSA):c.979+1G>A

dbSNP: rs754722529

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169323	SCV000220656	likely pathogenic	Metachromatic leukodystrophy	2014-08-28	criteria provided, single submitter	literature only
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000169323	SCV002054026	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169323	SCV002295965	pathogenic	Metachromatic leukodystrophy	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the ARSA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 14517960, 34276053, 34554397). This variant is also known as c.973+1G>A. ClinVar contains an entry for this variant (Variation ID: 188949). 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.
GeneDx	RCV003151752	SCV003840880	pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing	Reported as c.973+1 G>A and seen with a second ARSA variant, phase unknown, in a patient with juvenile MLD in the published literature (Eng et al., 2003); Canonical splice site variant predicted to result in a null allele 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: 34554397, 34276053, 14517960)
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	RCV000169323	SCV001478468	likely pathogenic	Metachromatic leukodystrophy		no assertion criteria provided	clinical testing