Submissions for variant NM_002225.5(IVD):c.464GTG[3] (p.Gly156dup)

dbSNP: rs796051982

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185985	SCV000238944	likely pathogenic	not provided	2014-02-07	criteria provided, single submitter	clinical testing	A c.476_478dupGTG sequence change that is likely pathogenic was identified in the IVD gene. The normal sequence with the inserted bases in brackets is AGTG{GTG}AGTA. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The insertion of three nucleotides causes a insertion of a Glycine at amino acid position 159, denoted p.Gly159ins. The Glycine at position 159 is a highly conserved residue in the IVD protein that is located within a moderately conserved region of the protein. A missense mutation at this position (G159A) has been reported in association with isovaleric acidemia. Therefore, c.476_478dupGTG is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in IVD panel(s).
Invitae	RCV001040480	SCV001204056	uncertain significance	Isovaleryl-CoA dehydrogenase deficiency	2023-12-30	criteria provided, single submitter	clinical testing	This variant, c.476_478dup, results in the insertion of 1 amino acid(s) of the IVD protein (p.Gly159dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs796051982, gnomAD 0.009%). This variant has been observed in individual(s) with isovaleric acidemia (PMID: 31707166). This variant is also known as c.472_473insGTG (p.Ser158_Gly159insGly). ClinVar contains an entry for this variant (Variation ID: 203791). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000185985	SCV001468010	uncertain significance	not provided	2020-10-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001040480	SCV002060118	uncertain significance	Isovaleryl-CoA dehydrogenase deficiency	2021-11-03	criteria provided, single submitter	clinical testing	NM_002225.3(IVD):c.476_478dupGTG(G159dup) is an in-frame duplication classified as a variant of uncertain significance in the context of isovaleric acidemia. G159dup has been observed in cases with relevant disease (PMID: 31707166). Functional assessments of this variant are not available in the literature. G159dup has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, there is insufficient evidence to classify NM_002225.3(IVD):c.476_478dupGTG(G159dup) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Ambry Genetics	RCV002517825	SCV003701640	uncertain significance	Inborn genetic diseases	2022-04-13	criteria provided, single submitter	clinical testing	The c.476_478dupGTG (p.G159dup) alteration is located in exon 5 (coding exon 5) of the IVD gene. The alteration consists of an in-frame duplication of 3 nucleotides from position 476 to 478, resulting in the duplication of 1 residue. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV001040480	SCV004198027	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-11-22	criteria provided, single submitter	clinical testing