Submissions for variant NM_003060.4(SLC22A5):c.791C>G (p.Thr264Arg)

dbSNP: rs201262157

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526996	SCV000632571	pathogenic	Renal carnitine transport defect	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 264 of the SLC22A5 protein (p.Thr264Arg). This variant is present in population databases (rs201262157, gnomAD 0.008%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20574985, 35281663). ClinVar contains an entry for this variant (Variation ID: 460416). 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 SLC22A5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001566993	SCV001790597	likely pathogenic	not provided	2019-03-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate T264R is associated with significantly reduced carnitine transport (Frigeni et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20574985, 28841266)
Genome-Nilou Lab	RCV000526996	SCV002055758	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000526996	SCV002576616	likely pathogenic	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000526996	SCV002766214	likely pathogenic	Renal carnitine transport defect	2022-11-07	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.791C>G (p.Thr264Arg) results in a non-conservative amino acid change located in the major facilitator superfamily domain (IPR020846) of 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 3.2e-05 in 251456 control chromosomes (gnomAD). c.791C>G has been reported in the literature as a biallelic genotype in at least two individuals affected with Systemic Primary Carnitine Deficiency, identified through newborn screening programs (e.g. Li_2010, Martin-Rivada_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Frigeni_2017). Carnitine transport activity was reduced to < 3% of normal in cells expressing the variant, suggesting it negatively impacts protein function. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Three classified the variant as likely pathogenic and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000526996	SCV004201247	likely pathogenic	Renal carnitine transport defect	2023-11-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003900147	SCV004714550	likely pathogenic	SLC22A5-related disorder	2024-01-18	no assertion criteria provided	clinical testing	The SLC22A5 c.791C>G variant is predicted to result in the amino acid substitution p.Thr264Arg. This variant has been reported in the homozygous state in an individual with autosomal recessive carnitine deficiency (Li et al 2010. PubMed ID: 20574985). A functional assay indicates this variant results in ~2.5% enzyme activity in comparison to the wild-type protein (Frigeni M et al 2017. PubMed ID: 28841266). This variant was observed in a patient tested at PreventionGenetics with an additional pathogenic SLC22A5 variant and low carnitine levels (Internal Data). In summary, we categorize the c.791C>G variant as likely pathogenic.