Submissions for variant NM_000487.6(ARSA):c.1489_1492dup (p.Arg498fs)

dbSNP: rs774153480

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008371	SCV001168139	pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 12 amino acids are replaced with 75 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12809638)
Myriad Genetics, Inc.	RCV000169193	SCV002060162	likely pathogenic	Metachromatic leukodystrophy	2021-11-10	criteria provided, single submitter	clinical testing	NM_000487.5(ARSA):c.1489_1492dupCCCC(R498Pfs*76) is a read through frameshift variant classified as likely pathogenic in the context of metachromatic leukodystrophy. R498Pfs*76 has been observed in cases with relevant disease (PMID: 14517960). Functional assessments of this variant are not available in the literature. R498Pfs*76 has been observed in population frequency databases (gnomAD: NFE 0.016%). In summary, NM_000487.5(ARSA):c.1489_1492dupCCCC(R498Pfs*76) is a read through frameshift variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000169193	SCV003444495	pathogenic	Metachromatic leukodystrophy	2023-09-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the ARSA protein. Other variant(s) that result in a similarly extended protein product (p.Arg498Profs*75) have been determined to be pathogenic (PMID: 19021637, 26462614). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 188843). This variant is also known as 2590_2591insCCCC. This frameshift has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809638). This variant is present in population databases (rs774153480, gnomAD 0.005%). This sequence change results in a frameshift in the ARSA gene (p.Arg498Profs*76). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acid(s) of the ARSA protein and extend the protein by 63 additional amino acid residues.