ClinVar Miner

Submissions for variant NM_021150.4(GRIP1):c.1600A>C (p.Ile534Leu) (rs189438534)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767020 SCV000321758 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing The I534L variant in the GRIP1 gene was reported previously using alternate nomenclature I586L in an individual with autism and was absent in 480 control individuals (Mejias et al., 2011). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports I534L was observed in 13/8166 alleles from individuals of European American background, indicating it may be a rare variant in this population. The I534L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. The I534L variant caused increased interaction, faster recycling, and increased surface distribution of glutamate receptor in live, transfected hippocampal neurons, suggesting gain-of-function (Mejias et al., 2011). We interpret I534L as a variant of uncertain significance.
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000678296 SCV000804354 uncertain significance FRASER SYNDROME 3 2018-01-29 criteria provided, single submitter provider interpretation This is a 12 year old male with intellectual disability, autism spectrum disorder, mild hyptonia, hyperkinesis, and sleep problems. He has no history of seizures. This p.Ile534Leu variant is present in gnomAD non-Finnish European population at 0.22%. Computational prediction models are inconsistent. This patient does not have congenital anomalies that would be consistent with Fraser syndrome. This variant has been reported as a possible modifier of autism (Mejias, 2011) using alternate nomenclature (I586L). Whole exome sequencing identified a likely pathogenic, de novo variant in SCN2A and 1 additional variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255801 SCV000862616 likely benign not specified 2018-08-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000678296 SCV001267517 uncertain significance FRASER SYNDROME 3 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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