ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3517G>A (p.Glu1173Lys) (rs756029120)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169445 SCV000220864 likely pathogenic Wilson disease 2014-11-06 criteria provided, single submitter literature only
Invitae RCV000169445 SCV000626855 pathogenic Wilson disease 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1173 of the ATP7B protein (p.Glu1173Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs756029120, ExAC 0.001%). This variant has been observed as homozygous and as compound heterozygous in multiple individuals affected with Wilson disease (PMID: 10544227, 23843956, 23275100, 27022412, 17680703, Invitae). ClinVar contains an entry for this variant (Variation ID: 189050). Experimental studies have shown that this variant impacts the function of the encoded protein in vitro (PMID: 20333758). In summary, this variant is a rare missense change which has been observed in multiple affected individuals with evidence of functional impact. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169445 SCV000694448 pathogenic Wilson disease 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.3517G>A (p.Glu1173Lys) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the HAD-like domain and P-type ATPase, cytoplasmic domain N (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC and control cohorts in the literature at a frequency of 0.0000082 (1/121248 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). Multiple publications have reported the variant in Wilson disease patients. One study that provided familial genotyping data to confirm inheritance of the variant of interest along with a second pathogenic allele (Lee_TP7B_JHG_2000). One clinical diagnostic laboratory and several reputable databases have classified this variant as likely pathogenic or pathogenic. Taken together, this variant is classified as pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000169445 SCV000915633 pathogenic Wilson disease 2018-08-16 criteria provided, single submitter clinical testing The ATP7B c.3517G>A (p.Glu1173Lys) missense variant has been reported in seven studies in which it is found in a compound heterozygous state in at least seven patients and in a heterozygous state in at least eight patients, all with Wilson disease (Loudianos et al. 1999; Lee et al. 2000; Chappuis et al. 2007; Geng et al. 2013; Gu et al. 2013; Cheng et al. 2014; Dong et al. 2016). In at least one family in which the patient was compound heterozygous for the p.Glu1173Lys variant and a missense variant, the unaffected sister and father were identified to be heterozygous for the p.Glu1173Lys variant while the unaffected mother was heterozygous for the other missense variant. This variant was absent from at least 77 controls and is reported at a frequency of 0.000012 in the total population from the Genome Aggregation Database. Based on the evidence, the p.Glu1173Lys variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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