ClinVar Genomic variation as it relates to human health

Identified in individuals with suspected primary carnitine deficiency, however detailed clinical information was not provided (Rasmussen et al., 2014; Frigeni et al., 2017); Functional analysis found A44V is associated with significantly impaired carnitine transport (Frigeni et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23963628, 34426522, 28841266, 23653224)

Variant summary: SLC22A5 c.131C>T (p.Ala44Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 245048 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.131C>T has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (e.g., Rasmussen_2014b, Gallant_2017, Frigeni_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing that the variant protein displayed 8.22% of transport activity relative to wild-type OCTN2 (e.g, Frigeni_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28711408, 23653224, 23963628, 27896095, 34637945). Five ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: 2 submitters classified the variant as likely pathogenic, and 3 submitters classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 44 of the SLC22A5 protein (p.Ala44Val). This variant is present in population databases (rs199689597, gnomAD 0.006%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 23963628, 28711408). ClinVar contains an entry for this variant (Variation ID: 573546). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC22A5 protein function. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.