ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.122A>G (p.Asn41Ser) (rs201738967)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000145251 SCV000192309 likely pathogenic Wilson disease 2016-07-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000416017 SCV000331624 likely pathogenic not provided 2016-04-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416017 SCV000493245 likely pathogenic not provided 2016-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000416017 SCV000568299 likely pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing The N41S variant in the ATP7B gene has been reported previously in the heterozygous state in patients with Wilson disease who were heterozygous for another variant, and in one individual who was found to have three heterozygous ATP7B variants, however the phase of these variants in these patients was not provided (Deguti et al., 2004; Coffey et al., 2013). Functional studies indicate that cells expressing N41S have severely disabled protein targeting and retention (Braiterman et al., 2009). The N41S variant is observed in 27/66736 (0.04%) alleles from individuals of European non-Finnish background in the ExAC dataset (Lek et al., 2016). The N41S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret N41S as a likely pathogenic variant.
Invitae RCV000145251 SCV000626829 pathogenic Wilson disease 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 41 of the ATP7B protein (p.Asn41Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs201738967, ExAC 0.04%). This variant has been reported in individuals affected with clinical and biochemical features of Wilson disease (PMID: 15024742, 23518715, 22677543, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 157928). Experimental studies have shown that this missense change disrupts copper-sensitive targeting of the ATP7B protein function in vitro (PMID: 19033537, 21454443). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000416017 SCV000883435 likely pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing The ATP7B c.122A>G; p.Asn41Ser variant (rs201738967) has been described in at least 3 individuals affected with Wilsons disease, with a second pathogenic ATP7B variant described in 2 of them (Bost 2012, Coffey 2013, Deguti 2004). It is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 157928) and observed in the general population at an overall frequency of 0.022% (62/277062 alleles) in the Genome Aggregation Database. The asparagine at codon 41 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, in vitro functional analysis of this variant protein demonstrates severely disabled protein targeting and retention (Braiterman 2009). Based on available information, this variant is considered likely pathogenic. References: Bost M et al. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol. 2012 Jun;26(2-3):97-101. Braiterman L et al. Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B. Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G433-44. Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Deguti M et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398.
Fulgent Genetics,Fulgent Genetics RCV000145251 SCV000893331 likely pathogenic Wilson disease 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000145251 SCV000914631 likely pathogenic Wilson disease 2018-08-16 criteria provided, single submitter clinical testing The ATP7B c.122A>G (p.Asn41Ser) missense variant has been reported in two studies in which it is found in a compound heterozygote state in a total of three patients with Wilson disease. In one of the three patients, the p.Asn41Ser variant was detected in cis with a second missense variant and a third missense variant in trans (Deguti et al. 2004; Coffey et al. 2013). The p.Asn41Ser variant was absent from 60 controls (Deguti et al. 2004) and is reported at a frequency of 0.00048 in the European American population of the Exome Sequencing Project. Functionally, Braiterman et al. (2009) demonstrated that the p.Asn41Ser variant protein was defective in proper targeting and retention in WIF-B cells, when compared to wild type. Based on the evidence, the p.Asn41Ser variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000145251 SCV001163826 likely pathogenic Wilson disease 2020-02-13 criteria provided, single submitter clinical testing ATP7B c.122A>G (p.Asn41Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 249566 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00024 vs 0.0054), allowing no conclusion about variant significance. c.122A>G has been reported in the literature in individuals affected with Wilson Disease (e.g. Deguti_2004, Bost_2012, Ben-Rebah_2012, Coffey_2013). These data indicate that the variant is likely to be associated with disease. The variant has also been found, however, in compound heterozygosity with another pathogenic variant (p.Arg1319X) in a 43-year old individual who was asymptomatic (Brunet_2012). At least one publication reports experimental evidence evaluating an impact on protein function, and suggests that the variant impairs copper-sensitive ATP7B protein targeting and retention (Braiterman_2009). Eight ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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