Submissions for variant NM_015272.5(RPGRIP1L):c.251G>A (p.Arg84Gln)

gnomAD frequency: 0.00060  dbSNP: rs151212590

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000310412	SCV000397851	uncertain significance	Joubert syndrome 7	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000346684	SCV000397852	uncertain significance	Nephronophthisis 8	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000398312	SCV000397853	uncertain significance	Meckel syndrome, type 5	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464407	SCV000544802	likely benign	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765298	SCV000896553	uncertain significance	COACH syndrome 1; Joubert syndrome 7; Meckel syndrome, type 5	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001562186	SCV001784913	uncertain significance	not provided	2021-08-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV001562186	SCV003811889	uncertain significance	not provided	2020-05-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828321	SCV002089240	uncertain significance	Familial aplasia of the vermis	2020-08-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537804	SCV004114935	uncertain significance	RPGRIP1L-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The RPGRIP1L c.251G>A variant is predicted to result in the amino acid substitution p.Arg84Gln. This variant has been reported in three individuals with obesity (Melendez-Montañez and De Jesus-Rojas. 2024. PubMed ID: 38674329). This variant is reported in 0.062% of alleles in individuals of African descent in gnomAD, which is likely too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.