Submissions for variant NM_000053.4(ATP7B):c.3693_3697delinsTCTGGTACATTAACATTAA (p.Thr1232_Gln1233delinsLeuValHisTer)

dbSNP: rs1957151127

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175530	SCV001339144	likely pathogenic	Wilson disease	2020-03-04	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3693_3697delinsTCTGGTACATTAACATTAA (also known as c.3693_3697delins19, p.Thr1232LeufsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249572 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3693_3697delinsTCTGGTACATTAACATTAA in individuals affected with Wilson Disease and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001175530	SCV004361957	pathogenic	Wilson disease	2023-06-23	criteria provided, single submitter	clinical testing	This variant replaces 5 nucleotides in exon 17 of the ATP7B gene with 19 novel nucleotides (c.3693_3697delinsTCTGGTACATTAACATTAA), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with ATP7B-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV001175530	SCV004480553	pathogenic	Wilson disease	2022-08-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 918134). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1232Leufs*4) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883).