Submissions for variant NM_003361.4(UMOD):c.197T>C (p.Leu66Pro)

dbSNP: rs1567311288

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV002251377	SCV001434944	likely pathogenic	Familial juvenile hyperuricemic nephropathy type 1	2018-10-19	criteria provided, single submitter	clinical testing	The c.197T>C (p.Leu66Pro) variant in the UMOD gene has been reported in one patient with familial interstitial nephropathy (Xia et al., 2015 and reviewed in 29569962). This variant is identified in a patient with clinical diagnosis of familial autosomal dominant tubulointerstitial kidney disease referred for genetic testing in our laboratory. This variant has never been reported in general population databases and is located in a region where most of the variants associated with kidney disease are reported (PMID 28781372). Multiple lines of algorithms predict deleterious effect of the p.Leu66Pro change. Therefore, this c.197T>C (p.Leu66Pro) variant in the UMOD gene is classified as likely pathogenic.
Invitae	RCV000681880	SCV003461942	uncertain significance	not provided	2022-02-20	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 562408). This missense change has been observed in individual(s) with hyperuricemic nephropathy (PMID: 33574344). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 66 of the UMOD protein (p.Leu66Pro).
GeneDx	RCV000681880	SCV003840614	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31068150, 29569962, 31447099, 33574344, 30586318)
3billion	RCV002251377	SCV003842049	likely pathogenic	Familial juvenile hyperuricemic nephropathy type 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.64; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with UMOD related disorder (ClinVar ID: VCV000562408). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Gharavi Laboratory, Columbia University	RCV000681880	SCV000809359	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research