ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1995G>A (p.Met665Ile) (rs72552259)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000145256 SCV000192316 uncertain significance Wilson disease 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000498564 SCV000331190 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000145256 SCV000384671 uncertain significance Wilson disease 2017-09-12 criteria provided, single submitter clinical testing The ATP7B c.1995G>A (p.Met665Ile) missense variant has been reported in at least six studies in which it is found in a compound heterozygous state in three individuals, including two individuals with a diagnosis of Wilson disease and one young child who was asymptomatic, in one individual with Wilson disease where zygosity is not stated and in at least two additional patient alleles. The variant was also found in a heterozygous state in five unaffected individuals, and in six of 2100 control chromosomes (Loudianos et al. 1998; Lepori et al. 2012; Bost et al. 2012; Coffey et al. 2013; Van Biervliet et al. 2015; Dopazo et al. 2016). The p.Met665Ile variant is reported at a frequency of 0.006403 in the Ashkenazi Jewish population of the Genome Aggregation Database; this database also reports two individuals who are homozygous for this variant. At this time, it is unknown if these individuals can be explained by reduced penetrance, mild or late onset of symptoms, or if this is evidence supporting a benign classification of the p.Met665Ile variant. Based on the available evidence, the p.Met665Ile 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.
GeneDx RCV000498564 SCV000589307 likely pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing The M665I variant in the ATP7B gene has been reported previously in multiple individuals with Wilson disease, including at least two individuals who had another pathogenic variant on the opposite allele (in trans) (Loudianos et al., 1998; Weiss et al., 2010; Lepori et al., 2012; Bost et al., 2012; Coffey et al., 2013; van Biervliet et al., 2015). The M665I variant is observed in 65/10,152 (0.64%) alleles from individuals of Ashkenazi Jewish background and 394/276,832 (0.14%) total alleles, including two unrelated homozygous individuals, in large population cohorts (Lek et al., 2016). The M665I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret M665I as a likely pathogenic variant.
Invitae RCV000145256 SCV000626835 likely benign Wilson disease 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855573 SCV000694411 uncertain significance not specified 2019-03-11 criteria provided, single submitter clinical testing Variant summary: ATP7B c.1995G>A (p.Met665Ile) results in a conservative amino acid change located in the transmembrane domain 1 of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 278932 control chromosomes, including 2 homozygotes, predominantly at a frequency of 0.0064 within the Ashkenazi Jewish subpopulation in the gnomAD database and publications. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 1.2-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054), suggesting that the variant might be a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. The variant, c.1995G>A, has been reported in the literature in individuals affected with Wilson Disease (Bost_2012, Coffey_2013, Lepori_2012, Loudianos_1998, VanBiervliet_2015), however, the second mutation is not provided for most of them and only one study performed MLPA test to screen for a large deletion/duplication. Other missense changes at the same codon, p.Met665Val and p.Met665Arg, have been classified as variant of uncertain significance by our laboratory. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS x4, likely pathogenic x2, likely benign x1). In the light of available patient data, it is not certain whether this variant represents a very mild mutation resulting in a slight aberration in Cu metabolism leading to an atypical presentation or later onset of WD. Additional information, such as a phenotypical and biochemical data, preferably from a homozygous individual, is needed to ascertain this variant with confidence. A presence of two homozygotes in the gnomAD database may indicate a reduced penetrance or a late onset of subclinical cases. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000145256 SCV000746784 likely pathogenic Wilson disease 2017-12-18 criteria provided, single submitter clinical testing
Counsyl RCV000145256 SCV000800461 uncertain significance Wilson disease 2018-06-07 criteria provided, single submitter clinical testing
Mendelics RCV000145256 SCV001139357 likely pathogenic Wilson disease 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000498564 SCV001150659 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000145256 SCV001157315 uncertain significance Wilson disease 2018-10-23 criteria provided, single submitter clinical testing The ATP7B c.1995G>A, p.Met665Ile variant (rs72552259) is reported in the literature in multiple individuals affected with Wilson disease (Bost 2012, Coffey 2013, Ferenci 2014, Lepori 2012, Loudianos 1998, Van Biervliet 2015, Weiss 2010). This variant is reported in ClinVar (Variation ID: 157933), and is found in the general population with an overall allele frequency of 0.15% (408/280,594 alleles, including a single homozygote) in the Genome Aggregation Database. The methionine at codon 665 is moderately conserved, and computational algorithms (PolyPhen-2: benign; SIFT: damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Met665Ile variant is uncertain at this time. 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. Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013; 136(Pt 5):1476-87. Ferenci P et al. Phenotype-genotype correlations in patients with Wilson's disease. Ann N Y Acad Sci. 2014 May;1315:1-5. Lepori MB et al. Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis. Mol Cell Probes. 2012 Aug;26(4):147-50. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998; 12(2):89-94. Van Biervliet S et al. Clinical zinc deficiency as early presentation of Wilson disease. J Pediatr Gastroenterol Nutr. 2015;60(4):457-9. Weiss KH et al. Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S233-40.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415012 SCV000492604 uncertain significance Epileptic encephalopathy 2016-03-15 no assertion criteria provided clinical testing

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