Submissions for variant NM_015272.5(RPGRIP1L):c.1939G>A (p.Val647Ile)

gnomAD frequency: 0.00003  dbSNP: rs145572901

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802680	SCV000942521	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 647 of the RPGRIP1L protein (p.Val647Ile). This variant is present in population databases (rs145572901, gnomAD 0.03%). This missense change has been observed in individual(s) with Leber congenital amaurosis who had another genetic cause of disease (PMID: 19430481). ClinVar contains an entry for this variant (Variation ID: 648041). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RPGRIP1L function (PMID: 19430481). 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	RCV002487702	SCV002781711	uncertain significance	Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3	2024-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056570	SCV005726703	uncertain significance	not specified	2024-11-18	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1L c.1939G>A (p.Val647Ile) results in a conservative amino acid change located in the First C2 domain of RPGR-interacting protein 1 (IPR021656) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251236 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders (5.6e-05 vs 0.00079), allowing no conclusion about variant significance. c.1939G>A has been reported in the literature in an individual affected with Joubert Syndrome And Related Disorders (Khanna_2009). This report does not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. Co-occurrences with other pathogenic variant(s) have been reported (CRB1 c.2843G>A, p.Cys948Tyr), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 19430481). ClinVar contains an entry for this variant (Variation ID: 648041). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001825585	SCV002085713	uncertain significance	Familial aplasia of the vermis	2020-12-15	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004733047	SCV005352626	uncertain significance	RPGRIP1L-related disorder	2024-08-19	no assertion criteria provided	clinical testing	The RPGRIP1L c.1939G>A variant is predicted to result in the amino acid substitution p.Val647Ile. This variant has been reported in the heterozygous state along with a homozygous missense change in the CRB1 gene in an individual with ciliopathy (Khanna et al. 2009. PubMed ID: 19430481). This variant is reported in 0.033% of alleles in individuals of South 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.