ClinVar Miner

Submissions for variant NM_024598.4(USB1):c.215G>A (p.Arg72His)

dbSNP: rs372917091
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001822408 SCV002066782 uncertain significance not specified 2021-01-04 criteria provided, single submitter clinical testing DNA sequence analysis of the USB1 gene demonstrated a sequence change, c.215G>A, in exon 2 that results in an amino acid change, p.Arg72His. This sequence change does not appear to have been previously described in individuals with USB1-related disorders and has been described in the gnomAD database in two individuals with an overall population frequency of 0.0007% (dbSNP rs372917091). The p.Arg72His change affects a highly conserved amino acid residue located in a domain of the USB1 protein that is known to be functional. The p.Arg72His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg72His change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV001869751 SCV002143257 uncertain significance not provided 2023-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 72 of the USB1 protein (p.Arg72His). This variant is present in population databases (rs372917091, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with USB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1337810). 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 USB1 protein function with a positive predictive value of 80%. 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.
Ambry Genetics RCV002545165 SCV003596925 uncertain significance Inborn genetic diseases 2024-12-07 criteria provided, single submitter clinical testing The p.R72H variant (also known as c.215G>A), located in coding exon 2 of the USB1 gene, results from a G to A substitution at nucleotide position 215. The arginine at codon 72 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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