Submissions for variant NM_015272.5(RPGRIP1L):c.1810G>A (p.Glu604Lys)

gnomAD frequency: 0.00033  dbSNP: rs143863631

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726350	SCV000343997	uncertain significance	not provided	2016-08-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000303891	SCV000397814	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.
Illumina Laboratory Services, Illumina	RCV000361003	SCV000397815	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	RCV000264423	SCV000397816	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.
GeneDx	RCV000726350	SCV000566584	uncertain significance	not provided	2025-04-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29991045)
Fulgent Genetics, Fulgent Genetics	RCV000765294	SCV000896549	uncertain significance	COACH syndrome 1; Joubert syndrome 7; Meckel syndrome, type 5	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054615	SCV001218960	likely benign	Familial aplasia of the vermis; Meckel-Gruber syndrome	2025-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522007	SCV003684497	likely benign	Inborn genetic diseases	2022-12-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Natera, Inc.	RCV001833391	SCV002085716	uncertain significance	Familial aplasia of the vermis	2020-07-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004543128	SCV004781988	uncertain significance	RPGRIP1L-related disorder	2024-05-24	no assertion criteria provided	clinical testing	The RPGRIP1L c.1810G>A variant is predicted to result in the amino acid substitution p.Glu604Lys. This variant has been reported in the homozygous state in a patient with nephronophthisis-related ciliopathy, although pathogenicity was not determined (Kawaguchi et al. 2018. PubMed ID: 29991045). This variant is reported in 0.38% of alleles in individuals of Ashkenazi Jewish descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant has been reported in 0.01% of alleles in a subpopulation, including seven homozygous individuals. This variant has conflicting interpretations in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/289611/). 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.