Submissions for variant NM_000487.6(ARSA):c.109_116del (p.Asp37fs)

dbSNP: rs753415648

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670737	SCV000795630	likely pathogenic	Metachromatic leukodystrophy	2017-11-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000670737	SCV001360437	pathogenic	Metachromatic leukodystrophy	2019-05-13	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.109_116delGACCTGGG (p.Asp37LeufsX36) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.304delC(p.Leu102fsX6); c.960G>A(p.Trp320X)). The variant allele was found at a frequency of 1.2e-05 in 165594 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Draghia_1997, Virgens_2015). Three of these patients had infantile metachromatic leukodystrophy. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000670737	SCV001419379	pathogenic	Metachromatic leukodystrophy	2023-06-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 555003). This variant is also known as 103del8bp. This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9090526). 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 sequence change creates a premature translational stop signal (p.Asp37Leufs*36) 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).
Fulgent Genetics, Fulgent Genetics	RCV000670737	SCV002807791	pathogenic	Metachromatic leukodystrophy	2021-11-22	criteria provided, single submitter	clinical testing
GeneDx	RCV003328618	SCV004035588	pathogenic	not provided	2023-09-10	criteria provided, single submitter	clinical testing	Frameshift 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: 9090526, 31589614, 10477432)