Submissions for variant NM_015272.5(RPGRIP1L):c.3769G>A (p.Val1257Met)

gnomAD frequency: 0.00003  dbSNP: rs536037779

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001115444	SCV001273421	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	RCV001115445	SCV001273422	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	RCV001115446	SCV001273423	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243044	SCV001416176	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1257 of the RPGRIP1L protein (p.Val1257Met). This variant is present in population databases (rs536037779, gnomAD 0.06%). 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: 884393). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV002480487	SCV002776969	uncertain significance	Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3	2022-03-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833714	SCV002087490	uncertain significance	Familial aplasia of the vermis	2020-11-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538337	SCV004727034	uncertain significance	RPGRIP1L-related disorder	2024-08-22	no assertion criteria provided	clinical testing	The RPGRIP1L c.3769G>A variant is predicted to result in the amino acid substitution p.Val1257Met. To our knowledge, this variant has not been reported in the literature in individuals with RPGRIP1L-related disorders. This variant is reported in 0.056% of alleles in individuals of Latino descent in gnomAD. 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.