Submissions for variant NM_003060.4(SLC22A5):c.506G>A (p.Arg169Gln)

gnomAD frequency: 0.00003  dbSNP: rs121908889

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186134	SCV000239159	pathogenic	not provided	2022-09-25	criteria provided, single submitter	clinical testing	Functional analysis of R169Q found that it is associated with significantly reduced carnitine transport compared to wild-type (Frigeni et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 10425211, 20574985, 23090741, 21922592, 26828774, 28841266, 34178604, 33560599, 32853555)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006790	SCV000756761	pathogenic	Renal carnitine transport defect	2024-06-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the SLC22A5 protein (p.Arg169Gln). This variant is present in population databases (rs121908889, gnomAD 0.02%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 10425211, 20574985, 21922592, 23090741, 26828774). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6421). 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%. This variant disrupts the p.Arg169 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11058897, 12210323, 23090741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006790	SCV000920211	pathogenic	Renal carnitine transport defect	2018-04-10	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.506G>A (p.Arg169Gln) results in a conservative amino acid change that affects a highly conserved sequence motif in the encoded protein sequence (Burwinkel 1999). 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 4.5e-05 in 246204 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (4.5e-05 vs 0.0046), allowing no conclusion about variant significance. c.506G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Burwinkel 1999, Rose 2012, Yoon 2012). 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. The most pronounced variant effect results in <10% of normal activity (Rose 2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000006790	SCV001251478	pathogenic	Renal carnitine transport defect		criteria provided, single submitter	research	The SLC22A5 c.506G>A (p.R169Q) missense variant has been reported in the homozygous and compound heterozygous state in individuals with systemic primary carnitine deficiency (PMID: 10425211; 21922592; 23090741; 20574985).
Genome-Nilou Lab	RCV000006790	SCV002055806	pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006790	SCV004201284	pathogenic	Renal carnitine transport defect	2024-03-07	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000006790	SCV005051960	pathogenic	Renal carnitine transport defect	2024-02-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000006790	SCV005669199	pathogenic	Renal carnitine transport defect	2024-04-29	criteria provided, single submitter	clinical testing
OMIM	RCV000006790	SCV000026986	pathogenic	Renal carnitine transport defect	1999-08-02	no assertion criteria provided	literature only
Counsyl	RCV000006790	SCV000790502	likely pathogenic	Renal carnitine transport defect	2017-03-27	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000006790	SCV001462805	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing