ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2755C>G (p.Arg919Gly) (rs121907993)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000004061 SCV000220677 likely pathogenic Wilson disease 2014-09-09 criteria provided, single submitter literature only
Invitae RCV000004061 SCV000626846 pathogenic Wilson disease 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 919 of the ATP7B protein (p.Arg919Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs121907993, ExAC 0.02%). This variant has been observed as homozygous and as compound heterozygous in multiple individuals affected with Wilson disease with evidence of segregation (PMID: 21796144,17680703, 12376745, Invitae). ClinVar contains an entry for this variant (Variation ID: 3857). Experimental studies have been performed to assess the functional impact of this variant in vitro (PMID: 26032686). However, these results are not conclusive and their clinical significance is unclear. In summary, this variant is a rare missense change which has been observed in multiple affected individuals with evidence of disease co-segregation. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000004061 SCV000694428 pathogenic Wilson disease 2016-03-31 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" effect. The variant of interest was observed in the large, broad control population of ExAC with an allele frequency of 2/119980 (1/59990), predominantly in East Asians, 2/8592 (1/4296), which does not exceed the predicted maximum expected allele frequency for a pathogenic ATP7B variant of 1/185. The variant of interest has been reported in multiple affected individuals via publications in both homozygousand compound heterozygous states. A functional study does implicate the variant to negatively affect wild type function. In addition, a reputable clinical laboratory cites the variant as "likely pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
OMIM RCV000004061 SCV000024227 pathogenic Wilson disease 2002-01-01 no assertion criteria provided literature only

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