ClinVar Miner

Submissions for variant NM_015272.5(RPGRIP1L):c.3707G>A (p.Arg1236His)

gnomAD frequency: 0.00002  dbSNP: rs1410635948
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001307979 SCV001497411 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2023-07-03 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with RPGRIP1L-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPGRIP1L protein function. ClinVar contains an entry for this variant (Variation ID: 1010364). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1236 of the RPGRIP1L protein (p.Arg1236His).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002272447 SCV002557857 uncertain significance Joubert syndrome 7 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Meckel syndrome 5 (MIM#611561) and Joubert syndrome (MIM#7611560). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (161 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RPGR1 C-terminal domain (Pfam). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg1236Cys) variant has been reported in the ClinVar database and the literature in an individual with Meckel syndrome, but does not have sufficient evidence for pathogenicity (PMID: 19430481). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV002499586 SCV002805576 uncertain significance Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3 2024-06-14 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004531090 SCV004113942 uncertain significance RPGRIP1L-related disorder 2023-04-18 criteria provided, single submitter clinical testing The RPGRIP1L c.3707G>A variant is predicted to result in the amino acid substitution p.Arg1236His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-53639521-C-T). A different nucleotide substitution affecting the same amino acid (p.Arg1236Cys) has been reported in individuals with Meckel syndrome or subcortical heterotopia (Khanna et al. 2009. PubMed ID: 19430481; Uzquiano et al. 2019. PubMed ID: 31390572). At this time, the clinical significance of the c.3707G>A (p.Arg1236His) variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc. RCV001835507 SCV002087495 uncertain significance Familial aplasia of the vermis 2020-12-17 no assertion criteria provided clinical testing

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