Submissions for variant NM_015272.5(RPGRIP1L):c.962G>A (p.Arg321His)

gnomAD frequency: 0.00009  dbSNP: rs183419371

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000375576	SCV000336308	uncertain significance	not provided	2015-10-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001117358	SCV001275535	uncertain significance	Nephronophthisis 8	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001117359	SCV001275536	uncertain significance	Meckel syndrome, type 5	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001117360	SCV001275537	uncertain significance	Joubert syndrome 7	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241000	SCV001413989	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 321 of the RPGRIP1L protein (p.Arg321His). This variant is present in population databases (rs183419371, gnomAD 0.2%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 27434533). ClinVar contains an entry for this variant (Variation ID: 283929). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPGRIP1L protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002487213	SCV002794198	uncertain significance	Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3	2024-02-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000375576	SCV004010486	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017583	SCV004848450	likely benign	not specified	2020-08-11	criteria provided, single submitter	clinical testing	The p.Arg321His variant in RPGRIP1L is classified as likely benign due to lack of conservation among species (at least 3 primate species having a His at this position). It has also been identified in 0.14% (29/19946) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and computational prediction tools and conservation analyses suggest that it may not impact the protein. It has been reported in 1 compound heterozygous individual with Joubert syndrome; however, this individual also carried 2 variants in TMEM67 (Suzuki 2016 PMID: PMID: 27434533). ACMG/AMP Criteria applied: BP4_Strong, BS1_Supporting.
Natera, Inc.	RCV001833330	SCV002085747	uncertain significance	Familial aplasia of the vermis	2020-01-13	no assertion criteria provided	clinical testing
Neurology Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University	RCV001117360	SCV003803088	uncertain significance	Joubert syndrome 7		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535307	SCV004120631	uncertain significance	RPGRIP1L-related disorder	2024-01-09	no assertion criteria provided	clinical testing	The RPGRIP1L c.962G>A variant is predicted to result in the amino acid substitution p.Arg321His. This variant has been reported in the compound heterozygous state in an individual with Joubert syndrome and in the heterozygous state in an individual with adolescent idiopathic scoliosis (Suzuki et al. 2016. PubMed ID: 27434533; Supplementary Table 4, Jiang et al. 2020. PubMed ID: 32381728). This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.