Submissions for variant NM_015272.5(RPGRIP1L):c.628A>G (p.Asn210Asp)

gnomAD frequency: 0.00024  dbSNP: rs146584570

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489985	SCV000576957	uncertain significance	not provided	2018-02-27	criteria provided, single submitter	clinical testing	The N210D variant in the RPGRIP1L gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the N210D variant is observed in 4/6604 (0.061%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The N210D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N210D as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047354	SCV001211306	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 210 of the RPGRIP1L protein (p.Asn210Asp). This variant is present in population databases (rs146584570, gnomAD 0.1%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 29343940). ClinVar contains an entry for this variant (Variation ID: 426501). 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.
Illumina Laboratory Services, Illumina	RCV001118973	SCV001277299	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	RCV001118974	SCV001277300	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	RCV001118975	SCV001277301	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001118974	SCV001369323	uncertain significance	Joubert syndrome 7	2019-10-17	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply.
CeGaT Center for Human Genetics Tuebingen	RCV000489985	SCV001371360	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001118974	SCV001572166	uncertain significance	Joubert syndrome 7	2021-04-08	criteria provided, single submitter	research	The RPGRIP1L c.628A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002481554	SCV002775658	uncertain significance	Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3	2022-04-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155214	SCV003844934	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1L c.628A>G (p.Asn210Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 250950 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders (0.00031 vs 0.00079), allowing no conclusion about variant significance. c.628A>G has been reported in the literature in at least one individual affected with retinitis pigmentosa (Bryant_2018). This report does not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001273839	SCV001457424	uncertain significance	Familial aplasia of the vermis	2020-09-16	no assertion criteria provided	clinical testing