Submissions for variant NM_015272.5(RPGRIP1L):c.1331G>A (p.Arg444His)

gnomAD frequency: 0.00005  dbSNP: rs76600508

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000336182	SCV000397829	uncertain significance	Nephronophthisis 8	2018-01-12	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	RCV000397997	SCV000397830	uncertain significance	Joubert syndrome 7	2018-01-12	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	RCV000305923	SCV000397831	uncertain significance	Meckel syndrome, type 5	2018-01-12	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	RCV001068839	SCV001233972	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-10-13	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 444 of the RPGRIP1L protein (p.Arg444His). This variant is present in population databases (rs76600508, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with RPGRIP1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 319663). 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	RCV005010286	SCV005642116	uncertain significance	Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3	2024-04-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001273838	SCV001457422	uncertain significance	Familial aplasia of the vermis	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537801	SCV004118805	uncertain significance	RPGRIP1L-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The RPGRIP1L c.1331G>A variant is predicted to result in the amino acid substitution p.Arg444His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.047% 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.