Submissions for variant NM_015272.5(RPGRIP1L):c.685G>A (p.Ala229Thr)

gnomAD frequency: 0.04969  dbSNP: rs61747071

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000114223	SCV000171379	benign	not specified	2014-03-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Eurofins Ntd Llc (ga)	RCV000114223	SCV000231744	benign	not specified	2015-02-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000114223	SCV000312485	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094370	SCV000397839	benign	Joubert syndrome 7	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000332989	SCV000397840	benign	Meckel syndrome, type 5	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001094311	SCV000397841	benign	Nephronophthisis 8	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000473873	SCV000556988	benign	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001094370	SCV001737344	benign	Joubert syndrome 7	2021-06-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000114223	SCV002051288	benign	not specified	2021-12-20	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1L c.685G>A (p.Ala229Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.036 in 251116 control chromosomes, predominantly at a frequency of 0.11 within the African or African-American subpopulation in the gnomAD database, including 73 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 139.14 fold of the estimated maximal expected allele frequency for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders phenotype (0.00079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002293972	SCV002587282	benign	Focal segmental glomerulosclerosis	2022-09-09	criteria provided, single submitter	clinical testing
OMIM	RCV000001133	SCV000021283	risk factor	Retinitis pigmentosa in ciliopathies, modifier of	2009-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000035002	SCV000058641	pathologic	Familial aplasia of the vermis	2012-03-29	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000114223	SCV000147780	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
GeneReviews	RCV000234815	SCV000292020	not provided	Nephronophthisis		no assertion provided	literature only
Natera, Inc.	RCV000035002	SCV001457423	benign	Familial aplasia of the vermis	2020-09-16	no assertion criteria provided	clinical testing
GeneReviews	RCV001094370	SCV001792276	not provided	Joubert syndrome 7		no assertion provided	literature only
Clinical Genetics, Academic Medical Center	RCV000114223	SCV001923971	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705578	SCV001927900	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000114223	SCV001975035	benign	not specified		no assertion criteria provided	clinical testing