ClinVar Miner

Submissions for variant NM_000326.5(RLBP1):c.141+2T>C

gnomAD frequency: 0.00001  dbSNP: rs760650165
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598659 SCV000709978 likely pathogenic not provided 2019-09-17 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11868161, 10102299, 25525159)
Illumina Laboratory Services, Illumina RCV000779175 SCV000915696 pathogenic RLBP1-Related Disorders 2018-10-23 criteria provided, single submitter clinical testing The RLBP1 c.141+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.141+2T>C variant, also known as IVS+2T>C, has been reported in two studies and is found in a total of nine probands from four families, including one in a homozygous state and eight in a compound heterozygous state (Morimura et al. 1999; Eichers et al. 2002). Eight of these probands had Newfoundland rod-cone dystrophy, and one compound heterozygote had retinitis punctata albescens. The variant is also found in a heterozygous state in eight unaffected family members of these probands (Morimura et al. 1999; Eichers et al. 2002). There is segregation data in a three-generation family with Newfoundland rod-cone dystrophy showing that the affected family members are either homozygous or compound heterozygous for the variant (Eichers et al. 2002). The c.141+2T>C variant was absent from 106 control chromosomes (Morimura et al. 1999; Eichers et al. 2002) and is reported at a frequency of 0.000018 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of splice donor variants and the evidence in the literature, the c.141+2T>C variant is classified as pathogenic for RLBP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000598659 SCV001473246 pathogenic not provided 2019-09-04 criteria provided, single submitter clinical testing The RLBP1 c.141+2T>C variant (rs760650165), also published as IVS3+2T>C, is reported in the medical literature in both the homozygous and compound heterozygous state in individuals with retinal dystrophy (Eichers 2002, Morimura 1999). The variant is reported in the ClinVar database (Variation ID: 503712) and is only found in 2 out of 251,384 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site, which is likely to negatively impact gene function. Considering available information, this variant is classified as pathogenic. References: Eichers ER et al. Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1. Am J Hum Genet. 2002 Apr;70(4):955-64. Morimura H et al. Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. Invest Ophthalmol Vis Sci. 1999 Apr;40(5):1000-4.
Invitae RCV000598659 SCV003441695 pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the RLBP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RLBP1 are known to be pathogenic (PMID: 2392416, 11301032, 21447491, 25429852). This variant is present in population databases (rs760650165, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with retinitis punctata albescens (PMID: 10102299, 11868161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS3+2 (GT to GC). ClinVar contains an entry for this variant (Variation ID: 503712). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV001800829 SCV000034222 pathogenic Newfoundland cone-rod dystrophy 2002-04-01 no assertion criteria provided literature only

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