Submissions for variant NM_000053.4(ATP7B):c.1922T>C (p.Leu641Ser)

gnomAD frequency: 0.00059  dbSNP: rs186924074

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587060	SCV000568298	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated that p.(L641S) behaved similarly to the wild-type protein (de Bie et al. 2007; Braiterman et al. 2014); This variant is associated with the following publications: (PMID: 15967699, 23518715, 17919502, 18371106, 22677543, 24253677, 30097039, 34426522, 32248359, 16088907, Cumpata2022[Review], 24706876, 34400371, 36096368, 34620762, 35132767)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001263514	SCV000694407	uncertain significance	not specified	2021-05-14	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1922T>C (p.Leu641Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 251632 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0005 vs 0.0054), allowing no conclusion about variant significance. The variant c.1922T>C has been reported in the literature in individuals affected with Wilson Disease (example: Cox_2005, Vrabelova_2005, Bost_2012, Ferenci_2019), however, in most of these cases no full gene sequencing was performed, and/or the other pathogenic variant in trans was not specified and/or phase was not provided. These data therefore do not allow clear conclusions about the variant significance. Publications also reported experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on protein localization, copper transport activity, and copper-responsive trafficking (Braiterman_2014) and no effect on interaction with COMMD1 (de Bie_2007). Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000631248	SCV000752272	uncertain significance	Wilson disease	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 641 of the ATP7B protein (p.Leu641Ser). This variant is present in population databases (rs186924074, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease (PMID: 15967699, 16088907, 22677543, 23518715, 34400371). ClinVar contains an entry for this variant (Variation ID: 420002). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 17919502, 24706876). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000587060	SCV001248429	uncertain significance	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000631248	SCV001267853	uncertain significance	Wilson disease	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000631248	SCV001440937	likely benign	Wilson disease	2019-01-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000631248	SCV001473412	uncertain significance	Wilson disease	2022-09-20	criteria provided, single submitter	clinical testing	The ATP7B c.1922T>C; p.Leu641Ser variant (rs186924074) is reported in the literature in individuals affected with Wilson disease (Bost 2012, Coffey 2013, Cox 2005, Vrabelova 2005). This variant is reported in ClinVar (Variation ID: 420002), and is found in the general population with an overall allele frequency of 0.046% (130/280986 alleles) in the Genome Aggregation Database. The leucine at codon 641 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.93). However, functional analyses of the variant protein show similar copper trafficking compared to wild type (Braiterman 2014, de Bie 2007). Due to conflicting information, the clinical significance of the p.Leu641Ser 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;26(2-3):97-101. PMID: 22677543. Braiterman LT et al. Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B. Proc Natl Acad Sci U S A. 2014;111(14):E1364-E1373. PMID: 24706876. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013;136(Pt 5):1476-1487. PMID: 23518715. Cox DW et al. Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Hum Mutat. 2005;26(3):280. PMID: 16088907. de Bie P et al. Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology. 2007;133(4):1316-1326. PMID: 17919502. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005;86(1-2):277-285. PMID: 15967699.
Mayo Clinic Laboratories, Mayo Clinic	RCV000587060	SCV001714454	uncertain significance	not provided	2021-01-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000631248	SCV001977178	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000631248	SCV002060319	uncertain significance	Wilson disease	2021-11-08	criteria provided, single submitter	clinical testing	NM_000053.3(ATP7B):c.1922T>C(L641S) is a missense variant classified as a variant of uncertain significance in the context of Wilson disease. L641S has been observed in cases with relevant disease (PMID: 30232804, 15967699, 16088907, 22677543). Functional assessments of this variant are available in the literature (PMID: 24706876, 17919502). L641S has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_000053.3(ATP7B):c.1922T>C(L641S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Ambry Genetics	RCV002525825	SCV003675423	uncertain significance	Inborn genetic diseases	2022-09-30	criteria provided, single submitter	clinical testing	The c.1922T>C (p.L641S) alteration is located in exon 6 (coding exon 6) of the ATP7B gene. This alteration results from a T to C substitution at nucleotide position 1922, causing the leucine (L) at amino acid position 641 to be replaced by a serine (S). The altered amino acid is conserved throughout evolution: The p.L641 amino acid is conserved in available vertebrate species. The p.L641S alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.