Submissions for variant NM_000203.5(IDUA):c.876del (p.Asp292fs)

dbSNP: rs1553917209

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547146	SCV000627152	pathogenic	Mucopolysaccharidosis type 1	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp292Glufs*25) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with MPS I (PMID: 7951228; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 456720). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV001007594	SCV001167273	likely pathogenic	Hurler syndrome	2019-09-06	criteria provided, single submitter	clinical testing	This IDUA variant is absent from large population datasets. A single submitter in ClinVar classifies this variant as pathogenic. This frameshift variant results in a premature stop codon in exon 7 likely leading to nonsense-mediated decay and lack of protein production. This variant is considered likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000547146	SCV001363957	pathogenic	Mucopolysaccharidosis type 1	2019-01-02	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.876delC (p.Asp292GlufsX25) 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.1205G>A (p.Trp402X), c.1210G>T (p.Glu404X), and c.1799delC (p.Ser600X)). The variant was absent in 204226 control chromosomes (gnomAD). c.876delC has been reported in the literature in an individual affected with Mucopolysaccharidosis Type 1 (Bunge_1994). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001266574	SCV001444750	pathogenic	Inborn genetic diseases	2019-07-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001788278	SCV002030923	pathogenic	not provided	2021-12-13	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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 8680403, 7951228)
Natera, Inc.	RCV000547146	SCV001461756	pathogenic	Mucopolysaccharidosis type 1	2020-09-16	no assertion criteria provided	clinical testing