Submissions for variant NM_003060.4(SLC22A5):c.1400C>G (p.Ser467Cys)

gnomAD frequency: 0.00009  dbSNP: rs60376624

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000414447	SCV000111945	pathogenic	not provided	2013-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000414447	SCV000490806	pathogenic	not provided	2022-05-19	criteria provided, single submitter	clinical testing	In vitro expression studies in HEK cells indicate that S467C has significantly reduced L-carnitine uptake relative to a normal control (Koizumi et al., 1999); 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: 28186590, 20208395, 25377941, 26589311, 25846890, 23090741, 12183691, 10545605, 26828774, 27317853, 29581464, 28841266, 20074989, 20574985, 29132460, 30885166, 30863740, 31637888, 32595695, 33757571, 33560599, 33181153)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022379	SCV000632528	pathogenic	Renal carnitine transport defect	2024-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 467 of the SLC22A5 protein (p.Ser467Cys). This variant is present in population databases (rs60376624, gnomAD 0.2%). This missense change has been observed in individuals with SLC22A5-related conditions (PMID: 10545605, 20074989, 20574985, 21922592, 23090741). ClinVar contains an entry for this variant (Variation ID: 25423). Invitae Evidence 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 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: 10545605, 12183691). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000022379	SCV001162982	pathogenic	Renal carnitine transport defect	2024-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000022379	SCV001193898	likely pathogenic	Renal carnitine transport defect	2020-01-03	criteria provided, single submitter	clinical testing	NM_003060.3(SLC22A5):c.1400C>G(S467C) is classified as likely pathogenic in the context of primary carnitine deficiency. Sources cited for classification include the following: PMID: 30904546, 28841266, 20074989, 23090741, 10545605 and 12183691. Classification of NM_003060.3(SLC22A5):c.1400C>G(S467C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000414447	SCV001247713	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000414447	SCV001433772	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing	The SLC22A5 c.1400C>G; p.Ser467Cys variant (rs60376624) has been described in the homozygous and compound heterozygous states in individuals affected with primary carnitine deficiency or carnitine uptake deficiency (Koizumi 1999, Li 2010, Rose 2012, Yoon 2012). It is reported as pathogenic in ClinVar (Variation ID: 25423) and observed in the East Asian population at an overall frequency of 0.2% (43/18870 alleles) in the Genome Aggregation Database. The serine at codon 467 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. Additionally, functional analyses of the variant protein demonstrate a significant reduction in L-carnitine uptake (Koizumi 1999, Rose 2012). Based on available information, this variant is considered pathogenic. References: Koizumi A et al. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet. 1999 Nov;8(12):2247-54. 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. Rose E et al. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012 Jan;33(1):118-23. Yoon Y et al. SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation. Ann Clin Lab Sci. 2012 Fall;42(4):424-8.
Revvity Omics, Revvity	RCV000022379	SCV002022599	pathogenic	Renal carnitine transport defect	2023-08-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000022379	SCV002055829	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022379	SCV002074341	pathogenic	Renal carnitine transport defect	2022-01-19	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1400C>G (p.Ser467Cys) 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 allele was found at a frequency of 0.00017 in 251468 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00017 vs 0.0046), allowing no conclusion about variant significance. c.1400C>G is a common pathogenic mutation found in individuals with primary carnitine deficiency or carnitine uptake defect (ie. Koizumi_1999, Lin_2020). In vitro functional analysis revealed the variant to reduce L-carnitine uptake to 11% of the normal control (Koizumi_2020). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000022379	SCV002790443	pathogenic	Renal carnitine transport defect	2024-04-03	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000022379	SCV004812654	pathogenic	Renal carnitine transport defect	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change in SLC22A5 is predicted to replace serine with serine at codon cysteine, p.(Ser467Cys). The serine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the transmembrane major facilitator superfamily (MFS) profile domain. There is a large physicochemical difference between serine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.2% (98/44,876 alleles) in the East Asian population. This variant has been detected in the homozygous and compound heterozygous state in multiple individuals with a diagnosis of systemic carnitine deficiency (SCD) mainly ascertained through newborn screening and asymptomatic (PMID: 20574985, 25846890, 21922592, 28841266, 37628339). The variant segregates with SCD in at least one family (PMID: 25846890). In vitro functional assays with limited validation in mammalian cell lines demonstrate the variant significantly reduces carnitine uptake (PMID: 10545605, 28841266). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.756). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1, PP3, PS3_Supporting.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000414447	SCV005198258	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000022379	SCV001462823	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000022379	SCV004800872	pathogenic	Renal carnitine transport defect		no assertion criteria provided	clinical testing	PS3+PM3_S+PP1_S+PP3+PP4