Submissions for variant NM_001366722.1(GRIP1):c.1756A>C (p.Ile586Leu)

gnomAD frequency: 0.00147  dbSNP: rs189438534

Total submissions: 11

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.
Eurofins Ntd Llc (ga)	RCV000255801	SCV000862616	likely benign	not specified	2018-08-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000255801	SCV002500179	likely benign	not specified	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: GRIP1 c.1600A>C (p.Ile534Leu) results in a conservative amino acid change located in the PDZ domain (IPR001478) of 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 0.0013 in 248122 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in GRIP1 causing Cryptophthalmos Syndrome phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1600A>C has been reported in the literature in two heterozygous brothers affected with autism; it had been inherited from their unaffected mother (Mejias_2010). Experimental evidence provided by the authors demonstrated the variant was associated with altered interactions with glutamate receptors 2/3 in a yeast two-hybrid assay and faster recycling and increased surface distribution of GluA2 in rat neurons. This report does not provide unequivocal conclusions about association of the variant with Cryptophthalmos Syndrome. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign for Cryptophthalmos Syndrome.
CeGaT Center for Human Genetics Tuebingen	RCV000767020	SCV002545050	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	GRIP1: BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000767020	SCV003264691	likely benign	not provided	2025-01-20	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000767020	SCV001743614	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000767020	SCV001932330	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000767020	SCV001971254	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003920025	SCV004728929	likely benign	GRIP1-related disorder	2021-08-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).