ClinVar Miner

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

gnomAD frequency: 0.00150  dbSNP: rs119465999
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Total submissions: 3
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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.
Invitae 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

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