Submissions for variant NM_000203.5(IDUA):c.1093C>G (p.Leu365Val)

gnomAD frequency: 0.00002  dbSNP: rs527336882

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000902904	SCV001047345	likely benign	Mucopolysaccharidosis type 1	2024-08-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000902904	SCV001319813	uncertain significance	Mucopolysaccharidosis type 1	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193754	SCV001362839	uncertain significance	not specified	2019-03-22	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.1093C>G (p.Leu365Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 261854 control chromosomes, predominantly at a frequency of 0.0025 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.00017 vs 0.0027), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1093C>G in individuals affected with Mucopolysaccharidosis Type 1 and no experimental evidence demonstrating its impact on protein function have 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 uncertain significance.
Revvity Omics, Revvity	RCV003132120	SCV003809909	uncertain significance	not provided	2022-01-03	criteria provided, single submitter	clinical testing
Pangenia Genomics, Pangenia Inc.	RCV000902904	SCV003925671	uncertain significance	Mucopolysaccharidosis type 1	2021-11-18	criteria provided, single submitter	research	The IDUA, c.1093C>G (p.Leu365Val) variant is at extremely low frequency in population database; allele frequency in East Asia population is 0.0025 by gnomAD v2.1.1. Multiple lines of computational evidence support a deleterious effect of this variant (REVEL = 0.768). There are multiple submissions of this variant in ClinVar (Variation ID: 728422) with conflicting interpretations.
Natera, Inc.	RCV000902904	SCV001457284	uncertain significance	Mucopolysaccharidosis type 1	2020-04-23	no assertion criteria provided	clinical testing