Submissions for variant NM_000053.4(ATP7B):c.670A>T (p.Ile224Phe)

gnomAD frequency: 0.00014  dbSNP: rs200563529

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000259729	SCV000384685	uncertain significance	Wilson disease	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755836	SCV000883432	uncertain significance	not provided	2018-04-09	criteria provided, single submitter	clinical testing	The ATP7B c.670A>T; p.Ile224Phe variant (rs200563529), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 312398). This variant is found in the general population with an overall allele frequency of 0.03% (90/277082 alleles) in the Genome Aggregation Database. The isoleucine at codon 224 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Ile224Phe variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779819	SCV000916637	uncertain significance	not specified	2018-09-28	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.670A>T (p.Ile224Phe) results in a non-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 0.00032 in 277082 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00032 vs 0.0054). The variant is predominantly found in the Ashkenazi Jewish subpopulation of gnomAD at a frequency of 0.0081, which is approximately 1.5 times higher than the maximal expected allele frequency, suggesting the variant may be a benign polymorphism found in Ashkenazi Jewish populations. However, since this is a relatively genetically isolated population, these data allow no conclusion about variant significance. To our knowledge, no occurrence of c.670A>T in individuals affected with Wilson Disease and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000259729	SCV000948994	likely benign	Wilson disease	2025-02-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000259729	SCV002027183	uncertain significance	Wilson disease	2021-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000755836	SCV002820542	uncertain significance	not provided	2024-06-18	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002520888	SCV003692503	likely benign	Inborn genetic diseases	2023-04-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Natera, Inc.	RCV000259729	SCV001456195	uncertain significance	Wilson disease	2020-04-15	no assertion criteria provided	clinical testing