ClinVar Genomic variation as it relates to human health

The RLBP1 c.677T>A (p.Met226Lys) missense variant has been reported in three studies in which it is found in a total of 25 patients with RLBP1-related disorders including in four patients in a homozygous state and in 21 patients in a compound heterozygous state (Morimura et al. 1999; Köhn et al. 2008; Burstedt et al. 2013). The p.Met226Lys variant was also found in two unaffected family members in a heterozygous state. The variant was present in a heterozygous state in one of 303 control samples and is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression in E.coli showed that the p.Met226Lys variant is less soluble than the wild type protein; NMR analysis of the protein structure showed that the variant protein has structural differences in comparison to wild type; UV-visible spectral analysis of purified protein showed that the variant protein has no cis-retinoid binding capacity for either 9-cis-retinal or 11-cis retinal. Overall the functional studies showed that the p.Met226Lys variant protein abolishes retinoid binding and impairs function of the protein in the visual cycle as an 11-cis retinol acceptor and substrate carrier (Golovleva et al. 2003). Based on the collective evidence, the p.Met226Lys 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.

Variant summary: RLBP1 c.677T>A (p.Met226Lys) results in a non-conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) 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 4.4e-05 in 251440 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RLBP1 causing Retinitis Pigmentosa (4.4e-05 vs 0.00063), allowing no conclusion about variant significance. c.677T>A has been reported in the literature in many compound heterozygous and homozygous individuals affected with Retinitis Pigmentosa and was shown to segregate with disease in related individuals (e.g., Kohn_2008, Morimura_1999, Thorsteinsson_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18344446, 10102299, 33851411). Five ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 4) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 226 of the RLBP1 protein (p.Met226Lys). This variant is present in population databases (rs137853291, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of retinitis punctata albescens (PMID: 10102299, 22551409). 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 M225K. ClinVar contains an entry for this variant (Variation ID: 13101). 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 not expected to disrupt RLBP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RLBP1 function (PMID: 12536144). For these reasons, this variant has been classified as Pathogenic.