ClinVar Miner

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

gnomAD frequency: 0.00025  dbSNP: rs201738967
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Total submissions: 19
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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
Eurofins Ntd Llc (ga) RCV000416017 SCV000331624 likely pathogenic not provided 2016-04-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000416017 SCV000493245 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000416017 SCV000568299 likely pathogenic not provided 2023-03-30 criteria provided, single submitter clinical testing Published functional studies demonstrate this variant is associated with impaired protein trafficking and apical targeting, supporting a damaging effect (Braiterman L et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20437613, 27535533, 17919502, 21454443, 22677543, 23518715, 22898812, 31589614, 34426522, 32248359, 15024742, 30275481, 30937429, 27377421, 28719003, 26740555, 27460824, 34620762, 34400371, 22820477, 19033537, 30097039, 32770663, 22106832, 26986070, 33640437, 31408533, 29473088, 29063292, 31059521, 36096368)
Invitae RCV000145251 SCV000626829 pathogenic Wilson disease 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 41 of the ATP7B protein (p.Asn41Ser). This variant is present in population databases (rs201738967, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical and biochemical features of Wilson disease (PMID: 15024742, 22677543, 23518715; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 157928). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 19033537, 21454443). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000145251 SCV000883435 likely pathogenic Wilson disease 2020-04-24 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 Wilson disease and two of these individuals carry a second pathogenic ATP7B variant (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 0.024% (68/280,840 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 2022-04-29 criteria provided, single submitter clinical testing
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000145251 SCV001163826 likely pathogenic Wilson disease 2022-01-21 criteria provided, single submitter clinical testing Variant summary: 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, Ben-Rebah_2012, Bost_2012,Coffey_2013, Woimant_2020 and Collins_2021). 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). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=4) and likely pathogenic (n=8). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000416017 SCV001448931 likely pathogenic not provided 2019-10-09 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000416017 SCV001713641 pathogenic not provided 2020-05-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000145251 SCV001977412 pathogenic Wilson disease 2021-08-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000145251 SCV002021992 likely pathogenic Wilson disease 2022-09-06 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000416017 SCV002502637 likely pathogenic not provided 2022-03-25 criteria provided, single submitter clinical testing
Mendelics RCV000145251 SCV002518560 pathogenic Wilson disease 2022-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002514798 SCV003572404 likely pathogenic Inborn genetic diseases 2022-01-08 criteria provided, single submitter clinical testing The c.122A>G (p.N41S) alteration is located in exon 2 (coding exon 2) of the ATP7B gene. This alteration results from an A to G substitution at nucleotide position 122, causing the asparagine (N) at amino acid position 41 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.02% (68/280840) total alleles studied. The highest observed frequency was 0.05% (61/128586) of European (non-Finnish) alleles. The p.N41S variant has been identified in multiple patients with Wilson disease with a second pathogenic ATP7B variant detected in trans or phase unknown in at least four of the reported cases (Ben-Rebeh, 2012; Bost, 2012; Brunet, 2012; Coffey, 2013; Deguti, 2004; Woimant, 2020). This amino acid position is highly conserved in available vertebrate species. Functional studies showed the p.N41S variant impairs apical targeting, Golgi retention, and ATP7B trafficking in vitro (Braiterman, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics RCV000145251 SCV004216258 likely pathogenic Wilson disease 2023-10-30 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000145251 SCV004362507 likely pathogenic Wilson disease 2023-10-25 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 41 of the ATP7B protein. This variant is located in the p.Phe37_Glu45 sequence that is thought to be an essential apical targeting determinant for ATP7B in elevated copper condition and participate in the post-trans-Golgi network retention of the protein under low-copper condition (PMID: 19033537). A functional study has reported that this variant results in defective copper-induced trafficking of ATP7B protein in hepatic cells (PMID: 19033537). This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 15024742, 22677543, 22820477, 23518715, 32770663, 33640437, 36096368; ClinVar: SCV000626829.6), including at least six individuals in the compound heterozygous state or unknown phase with a second pathogenic variant in the ATP7B gene (PMID: 15024742, 22820477, 23518715, 33640437). This variant has been identified in 68/280840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV000145251 SCV004041760 likely pathogenic Wilson disease 2023-10-09 no assertion criteria provided clinical testing

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