ClinVar Miner

Submissions for variant NM_015272.5(RPGRIP1L):c.3658A>G (p.Ile1220Val)

gnomAD frequency: 0.00026  dbSNP: rs147046186
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001240541 SCV001413496 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2022-09-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1220 of the RPGRIP1L protein (p.Ile1220Val). This variant is present in population databases (rs147046186, gnomAD 0.08%). 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: 965972). 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
GeneDx RCV001586080 SCV001810805 uncertain significance not provided 2020-07-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002480797 SCV002775682 uncertain significance Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3 2022-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002563977 SCV003526303 uncertain significance Inborn genetic diseases 2021-06-30 criteria provided, single submitter clinical testing The c.3658A>G (p.I1220V) alteration is located in exon 25 (coding exon 24) of the RPGRIP1L gene. This alteration results from a A to G substitution at nucleotide position 3658, causing the isoleucine (I) at amino acid position 1220 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV001828953 SCV002087498 uncertain significance Familial aplasia of the vermis 2020-08-24 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004538500 SCV004116734 uncertain significance RPGRIP1L-related disorder 2023-11-30 no assertion criteria provided clinical testing The RPGRIP1L c.3658A>G variant is predicted to result in the amino acid substitution p.Ile1220Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.084% of alleles in individuals of African descent in gnomAD, which may be too common to be an unreported primary cause of disease. Although we suspect that this variant may be benign, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence.

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