ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2165dup (p.Arg723fs) (rs768729972)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000194439 SCV000246744 pathogenic Wilson disease 2013-02-08 criteria provided, single submitter clinical testing
Counsyl RCV000194439 SCV000798839 pathogenic Wilson disease 2018-03-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000194439 SCV000916620 pathogenic Wilson disease 2018-01-18 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2165dupT (p.Arg723GlufsX32) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.778dupC, p.Gln260fsX10; c.845delT, p.Leu282fsX2; c.1145_1151delCCCAACT, p.Ser382fsX24). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/246180 control chromosomes at a frequency of 0.0000041 in gnomAD, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant was reported in multiple WD patients (Coffey_2013, Nanji_1997, Forbes_2014). In addition, one clinical diagnostic laboratory/reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000194439 SCV001205573 pathogenic Wilson disease 2019-01-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg723Glufs*32) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs768729972, ExAC 0.001%). This variant has been observed in individuals with Wilson disease and to segregate with disease in a family (PMID: 9199563, 24555712). This variant is also known as 2164insT in the literature. ClinVar contains an entry for this variant (Variation ID: 210483). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.

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