Submissions for variant NM_001366722.1(GRIP1):c.2381T>G (p.Met794Arg)

gnomAD frequency: 0.00155  dbSNP: rs144494437

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216399	SCV000270255	likely benign	not specified	2015-07-15	criteria provided, single submitter	clinical testing	p.Met742Arg in exon 18 of GRIP1: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (172/66736) of European chrom osomes (including one homozygote individual) by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144494437). It has been reported in 1 individual with autism and segregated with disease in 1 affected relative (Mejias 2011), however the proband was homozygous for the variant and the relati ve was heterozygous for the variant.
Eurofins Ntd Llc (ga)	RCV000726538	SCV000701569	uncertain significance	not provided	2016-10-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726538	SCV001096753	likely benign	not provided	2024-12-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726538	SCV001148779	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	GRIP1: BP4, BS2
Illumina Laboratory Services, Illumina	RCV001114156	SCV001272000	likely benign	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216399	SCV002556219	likely benign	not specified	2022-06-28	criteria provided, single submitter	clinical testing	Variant summary: GRIP1 c.2225T>G (p.Met742Arg) results in a non-conservative amino acid change located in the PDZ domain (IPR001478) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 280778 control chromosomes (gnomAD), with 2 homozygotes. The variant occurs predominantly at a frequency of 0.0027 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 (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2225T>G in individuals affected with Cryptophthalmos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, and five as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252265	SCV001428017	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000726538	SCV001931840	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726538	SCV001975779	likely benign	not provided		no assertion criteria provided	clinical testing