ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3688A>G (p.Ile1230Val) (rs200911496)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000331049 SCV000384649 uncertain significance Wilson disease 2016-06-14 criteria provided, single submitter clinical testing The c.3688A>G (p.Ile1230Val) variant has been reported in association with Wilson disease at least two patients in a compound heterozygous state (Davies et al. 2008; Denoyer et al. 2012). One patient was described as being asymptomatic, but showed slightly altered copper metabolism upon further serological and urine testing (Denoyer et al. 2012). This variant was absent from 53 control chromosomes from European individuals and is suggested to be in a well-conserved region (Davies et al. 2008). The p.Ile1230Val variant is reported at a frequency of 0.0005 in the European (Non-Finnish) population of the Exome Aggregation Consortium, including in one individual in a homozygous state. The evidence for this variant is limited. The p.Ile1230Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Wilson disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455157 SCV000538374 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: p.Ile1230Val in HGMD. Reported in one publication in patient(s) with Wilson disease (Davies 2008; full text not available). 0.1% in ExAC, including 1 homozygote.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000331049 SCV000584068 likely pathogenic Wilson disease 2015-02-10 criteria provided, single submitter research
Invitae RCV000331049 SCV000820313 uncertain significance Wilson disease 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1230 of the ATP7B protein (p.Ile1230Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200911496, ExAC 0.05%). This variant has been reported in an individual with Wilson disease (WD), and in an asymptomatic individual (PMID: 18373411, 23389864). ClinVar contains an entry for this variant (Variation ID: 312379). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757022 SCV000885049 likely pathogenic not provided 2018-04-03 criteria provided, single submitter clinical testing The ATP7B c.3688A>G; p.Ile1230Val variant (rs200911496) has been reported in at least two individuals in the compound heterozygous state (Davies 2008, Denoyer 2013). One individual with mild/asymptomatic Wilson disease had abnormal copper metabolic results and a right Kayser-Fleischer ring, but was otherwise asymptomatic with normal brain MRI (Denoyer 2013). This variant is reported in ClinVar (Variation ID: 312379), and found in the general population with an overall allele frequency of 0.03% (90/277234 alleles) in the Genome Aggregation Database. The isoleucine at codon 1230 is well conserved and lies in the ATPase domain. However, computational algorithms (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on the protein. Based on available information, this variant is considered likely pathogenic. REFERENCES Davies LP et al. New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genet Test. 2008 Mar;12(1):139-45. Denoyer Y et al. Neurological Wilson's disease lethal for the son, asymptomatic in the father. Mov Disord. 2013 Mar;28(3):402-3.
Integrated Genetics/Laboratory Corporation of America RCV000455157 SCV000916629 uncertain significance not specified 2020-07-24 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3688A>G (p.Ile1230Val) results in a conservative amino acid change located in the ATP loop of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 282682 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00034 vs 0.0054), allowing no conclusion about variant significance. c.3688A>G has been reported in the literature in individuals affected with Wilson Disease (Davies_2008, Denoyer_2013, Otto_2016) and one individual with developmental and/or intellectual delays (Bowling_2017). Denoyer_2013 reports the variant to occur in a family, which the proband diagnosed with Wilson Disease was a compound heterozygote for p.Glu127LysfsX26/p.Gly691Arg, and his father who was indicated to be asymptomatic although presenting with a right Kayser-Fleischer ring and alter copper levels, was a compound heterozygote for this variant (p.Ile1230Val) and p.Gly691Arg. These reports do not provide unequivocal conclusions about association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as uncertain significance.

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