Submissions for variant NM_003060.4(SLC22A5):c.1193C>T (p.Pro398Leu)

gnomAD frequency: 0.00006  dbSNP: rs144547521

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000224074	SCV000111942	pathogenic	not provided	2015-12-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000022365	SCV000220651	likely pathogenic	Renal carnitine transport defect	2014-08-27	criteria provided, single submitter	literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224074	SCV000281277	pathogenic	not provided	2015-06-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022365	SCV000819827	pathogenic	Renal carnitine transport defect	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 398 of the SLC22A5 protein (p.Pro398Leu). This variant is present in population databases (rs144547521, gnomAD 0.02%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 16652335, 20574985; Invitae). 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: 25411). 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%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 16652335). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000022365	SCV001433773	pathogenic	Renal carnitine transport defect	2021-10-20	criteria provided, single submitter	clinical testing	The SLC22A5 c.1193C>T; p.Pro398Leu variant (rs144547521) is reported in the literature in multiple individuals affected with primary carnitine deficiency (PCD), several of whom also carried an additional pathogenic variant (Amat di San Filippo 2006, Li 2010). The p.Pro398Leu variant is reported at pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 25411) and is observed in the general population at a low overall frequency of 0.01% (21/282862 alleles) in the Genome Aggregation Database. The proline at codon 398 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.515). Still, both in vitro and in vivo functional analyses of this variant demonstrate reduced cDNA expression and significantly decreased carnitine transport activity (Amat di San Filippo 2006, Frigeni 2017). Additionally, several other missense variants in the adjacent codon (p.Arg399Gln, p.Arg399Trp) are reported in individuals affected with PCD and exhibit reduced transport activity (Frigeni 2017), suggesting functional importance of this region of the protein. Based on available information, the p.Pro398Leu variant is considered to be pathogenic. References: Amat di San Filippo C et al. Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat. 2006 Jun;27(6):513-23. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Li F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010 Aug;31(8):E1632-51.
GeneDx	RCV000224074	SCV001803427	pathogenic	not provided	2024-09-13	criteria provided, single submitter	clinical testing	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: 23430858, 16652335, 25087612, 20574985, 23757202, 16602102, 28841266, 23379544, 35568002)
Revvity Omics, Revvity	RCV000022365	SCV002020649	pathogenic	Renal carnitine transport defect	2020-10-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000022365	SCV002055821	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022365	SCV004183399	pathogenic	Renal carnitine transport defect	2024-03-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224074	SCV004226146	pathogenic	not provided	2023-05-25	criteria provided, single submitter	clinical testing	PP4, PM2, PM3_strong, PS3, PS4_moderate
Natera, Inc.	RCV000022365	SCV001462820	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing