Submissions for variant NM_000053.4(ATP7B):c.1915C>T (p.His639Tyr)

gnomAD frequency: 0.00011  dbSNP: rs200728096

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597891	SCV000706740	uncertain significance	not provided	2017-03-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000670760	SCV000795656	uncertain significance	Wilson disease	2017-11-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000597891	SCV001714455	uncertain significance	not provided	2020-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000670760	SCV002027169	uncertain significance	Wilson disease	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307558	SCV002600357	uncertain significance	not specified	2022-10-02	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1915C>T (p.His639Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249584 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (5.6e-05 vs 0.0054), allowing no conclusion about variant significance. c.1915C>T has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual reportedly affected with Wilson Disease (example, Gromadzka_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease. At least one publication reports experimental evidence evaluating an impact on protein function (Braiterman_2014). These results showed no damaging effect of this variant on trafficking by demonstrating normal copper transport activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000670760	SCV002776825	uncertain significance	Wilson disease	2022-02-27	criteria provided, single submitter	clinical testing
Invitae	RCV000670760	SCV003442180	uncertain significance	Wilson disease	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 639 of the ATP7B protein (p.His639Tyr). This variant is present in population databases (rs200728096, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease or bipolar disorder (PMID: 16283883, 30556376). ClinVar contains an entry for this variant (Variation ID: 500690). 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 not expected to disrupt ATP7B protein function. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 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.
GeneDx	RCV000597891	SCV004028131	uncertain significance	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Published functional studies performed on patient fibroblast cells found this variant did not significantly impair copper transport activity (Braiterman LT et al., 2014); 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: 30556376, 18371106, 30032850, 16283883, 29564470, 24706876, 30230192)
Baylor Genetics	RCV000670760	SCV004216350	likely pathogenic	Wilson disease	2023-08-27	criteria provided, single submitter	clinical testing