ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1847G>A (p.Arg616Gln) (rs752850609)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667901 SCV000792424 pathogenic Wilson disease 2017-06-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000667901 SCV000918593 pathogenic Wilson disease 2018-04-30 criteria provided, single submitter clinical testing Variant summary: ATP7B c.1847G>A (p.Arg616Gln) results in a conservative amino acid change located in the Heavy metal-associated domain of 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 4.9e-05 in 246238 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4.9e-05 vs 0.0054), allowing no conclusion about variant significance. c.1847G>A has been reported in the literature in multiple individuals affected with Wilson Disease as both a compound heterozygous and homozygous allele (Loudianos_2003, Ljubic_2016). These data indicate that the variant is very likely to be associated with disease. 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 pathogenic.
Invitae RCV000667901 SCV000933962 pathogenic Wilson disease 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 616 of the ATP7B protein (p.Arg616Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs752850609, ExAC 0.009%). This variant has been observed to be homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 12885331, 21610751, 22735241, 26799313). ClinVar contains an entry for this variant (Variation ID: 552606). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198053 SCV001368838 pathogenic Seizures 2019-07-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. This variant was detected in homozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198139 SCV001368970 pathogenic mitochondrial 2019-04-09 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.

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