rs72552259
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_000053.4(ATP7B):c.1995G>A(p.Met665Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,894 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M665V) has been classified as Likely benign.
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.1995G>A | p.Met665Ile | missense_variant | 7/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.1995G>A | p.Met665Ile | missense_variant | 7/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00144 AC: 219AN: 152182Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00150 AC: 374AN: 249208Hom.: 1 AF XY: 0.00169 AC XY: 228AN XY: 135198
GnomAD4 exome AF: 0.00211 AC: 3090AN: 1461594Hom.: 10 Cov.: 31 AF XY: 0.00221 AC XY: 1605AN XY: 727102
GnomAD4 genome ? AF: 0.00144 AC: 219AN: 152300Hom.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 103AN XY: 74458
ClinVar
Submissions by phenotype
Wilson disease Uncertain:11Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 03, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 12, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 10, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Oct 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 07, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 06, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces methionine with isoleucine at codon 665 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Wilson disease (PMID: 9671269, 20517649, 22484412, 22677543, 23518715, 24517292, 25825851, 30232804, 32118851, 32154060, 33640437). In several of these individuals, this variant was reported in the compound heterozygous state (PMID: 23518715, 25825851, 32118851, 33640437). However, at least one individual carrying this variant in trans with a known pathogenic variant was asymptomatic (PMID: 32043565). This variant has been identified in 408/280594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 28, 2023 | The ATP7B c.1995G>A, p.Met665Ile variant (rs72552259) is reported in the literature in multiple individuals affected with Wilson disease, including in at least two individual with a pathogenic variant detected in trans (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, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.655). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 20, 2022 | This missense variant replaces methionine with isoleucine at codon 665 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Wilson disease (PMID: 9671269, 20517649, 22484412, 22677543, 23518715, 24517292, 25825851, 30232804, 32118851, 32154060, 33640437). In several of these individuals, this variant was reported in the compound heterozygous state (PMID: 23518715, 25825851, 32118851, 33640437). However, at least one individual carrying this variant in trans with a known pathogenic variant was asymptomatic (PMID: 32043565). This variant has been identified in 408/280594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 05, 2023 | Observed with a pathogenic variant on the opposite allele (in trans) in a patient with Wilson disease in the published literature, however the patient had an atypical phenotype and a variant in the MTIX gene that could be responsible for the clinical presentation (Van Biervliet et al., 2015); Observed with a second variant in published literature in multiple patients diagnosed with WD, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Ferenci et al., 2014; Nilles et al., 2023); 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: 20517649, 22677543, 9671269, 22692182, 26764160, 10447265, 22484412, 23518715, 32118851, 32154060, 32248359, 30275481, 33640437, 25825851, 32043565, 30097039, 36573661, 34620762, 24517292) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 29, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 04, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ATP7B: PM5, BS2 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 17, 2023 | Variant summary: ATP7B c.1995G>A (p.Met665Ile) results in a conservative amino acid change located in the TMA domain (Wallace_2020) 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 0.0015 in 251308 control chromosomes (including one homozygote), predominantly at a frequency of 0.0067 within the Ashkenazi Jewish subpopulation in the gnomAD database (v2, Exomes cohort). The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054), suggesting that the variant may be a benign polymorphism in populations of Ashkenazi Jewish origin. However, higher frequencies of pathogenic variants as well as later onset of disease and milder disease phenotypes have been noted in the literature in the Ashkenazi Jewish subpopulation (PMIDs: 32248359, 2382969, 13797909). c.1995G>A, has been reported in the literature in multiple compound heterozygous individuals affected with Wilson Disease (WD) with pathogenic variants in trans (e.g. Coffey_2013, VanBiervliet_2015, Ferenci_2019, Tampaki_2020, Collins_2021). However, for many WD individuals with the variant in the literature, a second mutation is not provided (e.g., Bost_2012, Lepori_2012, Loudianos_1998, Penon-Portmann_2020, Tampaki_2020). Other missense changes at the same codon, p.Met665Val and p.Met665Arg, have been classified as variants of uncertain significance by our laboratory. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 14 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=12), likely benign (n=1) and likely pathogenic (n=1). In light of available patient data, it is not certain whether this variant represents a relatively mild mutation resulting in a slight aberration in Cu metabolism leading to an atypical presentation or later onset of WD. The presence of three homozygotes in the gnomAD database (v2 & v3 combined) further support that this variant may result in reduced penetrance or a later onset of subclinical cases. Additional information, such as a phenotypical and biochemical data, preferably from a homozygous individual, is needed to ascertain this variant with confidence. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2024 | The c.1995G>A (p.M665I) alteration is located in exon 7 (coding exon 7) of the ATP7B gene. This alteration results from a G to A substitution at nucleotide position 1995, causing the methionine (M) at amino acid position 665 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Epileptic encephalopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 15, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at