ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.4301C>T (p.Thr1434Met) (rs60986317)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000251030 SCV000052027 likely benign not specified 2020-08-06 criteria provided, single submitter clinical testing Variant summary: ATP7B c.4301C>T (p.Thr1434Met) results in a non-conservative amino acid change in 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 0.002 in 249530 control chromosomes, including 1 homozygote, in the gnomAD database (v 2.1 exomes dataset). The variant was observed predominantly within the African or African-American subpopulation at a frequency of 0.0053. This frequency is close to the maximum expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0053 vs. 0.0054), suggesting that the variant might be benign. The variant, c.4301C>T, has been reported in the literature in individuals affected with Wilson Disease (Loudianos_1999, Abdelghaffar_2008, Lepori_2012) and other disease phenotypes (e.g. Vasta_2012, Demily_2017, Coutelier_2018). However, co-occurrences with other pathogenic variant have been reported (ATP7B homozygous c.3809A>G (p.Asn1270Ser); Abdelghaffar_2008) that could explain the patient's phenotype, thus providing supporting evidence for a benign role. A recent study found the variant in French residents, who were treated with indications other than Wilson Disease (WD), hepatic or neurological diseases, at a frequency of 0.00645 (i.e. 9/1394 alleles), whereas the variant was not found in their WD database, which included 496 index cases. Publications also reported experimental evidence evaluating an impact on protein function, and showed no damaging effect for this variant (Braiterman_2011, Hsi_2003). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (5x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224611 SCV000280605 uncertain significance not provided 2015-02-06 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
PreventionGenetics,PreventionGenetics RCV000251030 SCV000301725 benign not specified criteria provided, single submitter clinical testing
Invitae RCV000029379 SCV000626863 likely benign Wilson disease 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000029379 SCV000800724 uncertain significance Wilson disease 2017-04-18 criteria provided, single submitter clinical testing
Mendelics RCV000029379 SCV001139345 uncertain significance Wilson disease 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224611 SCV001156173 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197067 SCV001367702 uncertain significance Cerebellar ataxia; Muscle weakness; Dysarthria; Neurological speech impairment 2018-11-26 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PM5. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198138 SCV001368969 uncertain significance mitochondrial 2019-04-09 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PM5,PP2,PP3. This variant was detected in heterozygous state.

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