ClinVar Miner

Submissions for variant NM_015272.5(RPGRIP1L):c.3297_3298TC[3] (p.Ala1101fs) (rs797045104)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000190621 SCV000245657 likely pathogenic Joubert syndrome 7 2015-01-30 criteria provided, single submitter clinical testing The p.Ala1101SerfsX34 variant in RPGRIP1L has not been previously reported in individuals with RPGRIP1L-related disorders and data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1101 and leads to a premature termination codon 34 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of RPGRIP1L function is an established disease mechanism in RPGRIP1L-related disorders such as Joubert syndrome and Meckel syndrome (Delous 2007). Moreover, Rpgrip1l -/- mice show a similar phenotype to individuals affected with these disorders including polydactyly, craniofacial malformations, and left-right symmetry defects (Vierkotten 2007). In summary, although additional studies are required to fully establish its clinical significance, the p.Ala1101SerfsX34 variant is likely pathogenic.
Invitae RCV001209117 SCV001380538 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2019-11-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala1101Serfs*34) in the RPGRIP1L gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with RPGRIP1L-related conditions. Loss-of-function variants in RPGRIP1L are known to be pathogenic (PMID: 17558409). For these reasons, this variant has been classified as Pathogenic.

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