Submissions for variant NM_015272.5(RPGRIP1L):c.3764T>C (p.Ile1255Thr)

gnomAD frequency: 0.00001  dbSNP: rs749664648

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001367984	SCV001564358	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-04-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1255 of the RPGRIP1L protein (p.Ile1255Thr). This variant is present in population databases (rs749664648, gnomAD 0.02%). 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: 1058807). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
PreventionGenetics, part of Exact Sciences	RCV004531173	SCV004108946	uncertain significance	RPGRIP1L-related disorder	2022-10-05	criteria provided, single submitter	clinical testing	The RPGRIP1L c.3764T>C variant is predicted to result in the amino acid substitution p.Ile1255Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-53639464-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526845	SCV005039244	uncertain significance	not specified	2024-03-22	criteria provided, single submitter	clinical testing	Variant summary: RPGRIP1L c.3764T>C (p.Ile1255Thr) results in a non-conservative amino acid change located in the RPGRIP1, C-terminal domain (IPR041091) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3764T>C has been reported in the literature in a prenatal case affected with features of Joubert Syndrome who was compound heterozygous with a pathogenic variant (Huang_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36468023). ClinVar contains an entry for this variant (Variation ID: 1058807). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004952834	SCV005488040	uncertain significance	Inborn genetic diseases	2024-10-04	criteria provided, single submitter	clinical testing	The c.3764T>C (p.I1255T) alteration is located in exon 26 (coding exon 25) of the RPGRIP1L gene. This alteration results from a T to C substitution at nucleotide position 3764, causing the isoleucine (I) at amino acid position 1255 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001826066	SCV002087493	uncertain significance	Familial aplasia of the vermis	2020-03-02	no assertion criteria provided	clinical testing