Submissions for variant NM_003060.4(SLC22A5):c.505C>T (p.Arg169Trp)

dbSNP: rs121908890

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000006791	SCV000220523	likely pathogenic	Renal carnitine transport defect	2014-07-18	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006791	SCV000632554	pathogenic	Renal carnitine transport defect	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 169 of the SLC22A5 protein (p.Arg169Trp). This variant is present in population databases (rs121908890, gnomAD 0.0009%). This missense change has been observed in individuals with carnitine deficiency. Cultured skin fibroblasts collected from these individuals showed low carnitine uptake levels (PMID: 11058897, 12210323, 23090741, 28841266). ClinVar contains an entry for this variant (Variation ID: 6422). 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: 11058897). 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: 10425211, 20574985, 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	RCV000006791	SCV000920213	pathogenic	Renal carnitine transport defect	2018-04-20	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.505C>T (p.Arg169Trp) results in a non-conservative amino acid change located in the Major facilitator superfamily domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 4.1e-06 in 246214 control chromosomes (gnomAD). The variant, c.505C>T, has been reported in the literature in multiple individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Han_2014, Li_2010). Reported patients were found to have a significantly decreased transport activity (Frigeni_2017). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000006791	SCV001472128	pathogenic	Renal carnitine transport defect	2019-08-01	criteria provided, single submitter	clinical testing	The SLC22A5 c.505C>T; p.Arg169Trp variant (rs121908890) is reported in the literature in multiple individuals affected with primary carnitine deficiency (PCD), either in the homozygous state or in compound heterozygotes carrying a second pathogenic variant (Frigeni 2017, Lamhonwah 2002, Wang 2000). This variant is found on a single chromosome in the Genome Aggregation Database (1/251448 alleles), indicating it is not a common polymorphism. The arginine at codon 169 is highly conserved and is located in the glucose transporter signature motif implicated in transport activity (Wang 2000, Lamhonwah 2002). Consistent with this, functional studies indicate that the p.Arg169Trp variant exhibits substantially reduced carnitine transport activity in cultured cells and homozygous patient fibroblasts (Frigeni 2017, Wang 2000). Additionally, other amino acid substitutions at this codon (p.Arg169Gln, p.Arg169Pro) have been reported in individuals with PCD and are considered disease-causing (Frigeni 2017, Burwinkel 1999). Based on available information, the p.Arg169Trp variant is considered to be pathogenic. References: Burwinkel B et al. Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality. Biochem Biophys Res Commun. 1999 Aug 2;261(2):484-7. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Lamhonwah AM et al. Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy. Am J Med Genet. 2002 Aug 15;111(3):271-84. Wang Y et al. Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: lack of genotype-phenotype correlation. Hum Mutat. 2000 Nov;16(5):401-7.
Genome-Nilou Lab	RCV000006791	SCV002055805	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000006791	SCV003821064	pathogenic	Renal carnitine transport defect	2023-05-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006791	SCV004201281	pathogenic	Renal carnitine transport defect	2024-03-21	criteria provided, single submitter	clinical testing
OMIM	RCV000006791	SCV000026987	pathogenic	Renal carnitine transport defect	2000-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000006791	SCV001462804	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing