Submissions for variant NM_032830.3(UTP4):c.1693C>T (p.Arg565Trp)

gnomAD frequency: 0.00150  dbSNP: rs119465999

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000003345	SCV001435270	benign	Hereditary North American Indian childhood cirrhosis		criteria provided, single submitter	research	The homozygous p.Arg565Trp variant in CIRH1A has been identified in 22 relatives from 5 Ojibway-Cree families with North American Indian childhood cirrhosis and in the heterozygous state in 1 Qatari individual (PMID: 12417987, 24123366), but has also been identified in >1% of Latino chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg565Trp variant may not impact protein function (PMID: 16225863). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive North American Indian childhood cirrhosis.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851610	SCV002271752	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 565 of the UTP4 protein (p.Arg565Trp). This variant is present in population databases (rs119465999, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with North American Indian childhood cirrhosis (PMID: 12417987). ClinVar contains an entry for this variant (Variation ID: 3194). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt UTP4 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on UTP4 function (PMID: 16225863, 19732766, 20385600, 22916032). 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.
OMIM	RCV000003345	SCV000023503	uncertain significance	Hereditary North American Indian childhood cirrhosis	2015-03-05	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004751196	SCV005350817	uncertain significance	UTP4-related disorder	2024-05-21	no assertion criteria provided	clinical testing	The UTP4 c.1693C>T variant is predicted to result in the amino acid substitution p.Arg565Trp. This variant has been reported in the homozygous state in at least 34 individuals affected with progressive cholestasis of northwestern Quebec (Chagnon et al. 2002. PubMed ID: 12417987; Khendek et al. 2022. PubMed ID: 36133898). However, this variant is also reported in 1.8% of alleles in individuals of Latino descent in gnomAD, including 7 homozygous individuals. In vitro experimental studies on this variant have been inconclusive (Yu et al. 2005. PubMed ID: 16225863; Yu et al. 2009. PubMed ID: 19732766; Freed et al. 2012. PubMed ID: 22916032). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.