ClinVar Genomic variation as it relates to human health

Variant summary: LRPPRC c.1061C>T (p.Ala354Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251350 control chromosomes. c.1061C>T has been reported in the literature in many individuals affected with Leigh Syndrome, French-Canadian Type (examples- Mootha_2003, Debray_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that fibroblasts from patients homozygous for the variant demonstrated reduced levels of COX enzyme activity and a reduction in the synthesis of mitochondrial COX subunits (Sasarman_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

DNA sequence analysis of the LRPPRC gene demonstrated a sequence change, c.1061C>T, in exon 9 that results in an amino acid change, p.Ala354Val. This sequence change has been previously described in patients with Leigh syndrome in both homozygous and compund heterozygous state (PMID: 12529507). This sequence change has been reported as a founder variant for Leigh syndrome in the French-Canadian population (PMID: 12529507, 21266382). Experimental studies have shown that skin fibroblasts cell lines with this sequence change had reduced levels of LRPPRC protein expression in mitochondria (PMID: 15139850). This sequence change has been described in the gnomAD database with a low population frequency of 0.011% (dbSNP rs119466000) however, it has not been observed in homozygous state in any individuals. The p.Ala354Val change affects a moderately conserved amino acid residue located in a domain of the LRPPRC protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala354Val substitution. These collective evidences indicate that this sequence change is pathogenic.

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20200222, 17050673, 15139850, 12529507, 21266382, 25214534)

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 354 of the LRPPRC protein (p.Ala354Val). This variant is present in population databases (rs119466000, gnomAD 0.01%). This missense change has been observed in individual(s) with LRPPRC-related conditions (PMID: 21266382). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of French-Canadian ancestry (PMID: 12529507, 21266382). ClinVar contains an entry for this variant (Variation ID: 3110). 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 LRPPRC protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LRPPRC function (PMID: 15139850). For these reasons, this variant has been classified as Pathogenic.

The LRPPRC c.1061C>T variant is predicted to result in the amino acid substitution p.Ala354Val. The p.Ala354Val variant is considered a founder variant in French-Canadian populations and is highly prevalent in individuals with Leigh syndrome, French-Canadian type (LSFC) (Mootha et al. 2003. PubMed ID: 12529507; Debray et al. 2011. PubMed ID: 21266382). This variant has been reported in the homozygous state in almost every known LSFC patient (Mootha et al. 2003. PubMed ID: 12529507). In vitro functional studies have demonstrated that this variant leads to impaired LRPPRC protein function and reduced stability of mitochondrial mRNAs, leading to decreased expression of many mitochondrial proteins and Complex IV deficiency (Sasarman et al. 2010. PubMed ID: 20200222). Additional experiments noted tissue-specific phenotypic variability with skeletal muscle and liver cells more severely affected compared to heart tissue (Sasarman et al. 2015. PubMed ID: 25214534). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic.