ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs145572901
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Total submissions: 4
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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 2021-07-20 criteria provided, single submitter clinical testing
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.

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