Submissions for variant NM_003060.4(SLC22A5):c.136C>T (p.Pro46Ser)

gnomAD frequency: 0.00052  dbSNP: rs202088921

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000186152	SCV000224397	pathogenic	not provided	2017-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000186152	SCV000239178	pathogenic	not provided	2020-03-18	criteria provided, single submitter	clinical testing	Carnitine transport was significantly decreased in both skin fibroblasts from patients harboring P46S and in CHO cells overexpressing P46S (Frigeni et al., 2017; Rose et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31980526, 30609409, 21126579, 17126586, 29614331, 29111448, 23430858, 27896095, 26828774, 28711408, 28841266, 23653224, 21922592, 20574985, 20027113, 23520115, 22989098, 23430798, 23963628)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000173299	SCV000605131	pathogenic	Renal carnitine transport defect	2021-02-05	criteria provided, single submitter	clinical testing	The SLC22A5 c.136C>T; p.Pro46Ser variant (rs202088921) is reported in the literature in a homozygous or compound heterozygous state in multiple individuals with primary carnitine deficiency (de Boer 2013, Filippo 2011, Frigeni 2017, Rasmussen 2014, Schimmenti 2007). Functional analyses of the variant protein show reduced transport to the cell membrane and substantially reduced carnitine transport activity (Filippo 2011, Frigeni 2017, Rose 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 193250), and it is found in the general population at a frequency of 0.04% (118/275568 alleles) in the Genome Aggregation Database. The proline at codon 46 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.899). Based on available information, this variant is considered to be pathogenic. References: de Boer L et al. Primary Carnitine (OCTN2) Deficiency Without Neonatal Carnitine Deficiency. JIMD Rep. 2013;10:39-40. Filippo CA et al. Glycosylation of the OCTN2 carnitine transporter: study of natural mutations identified in patients with primary carnitine deficiency. Biochim Biophys Acta. 2011 Mar;1812(3):312-20. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Rasmussen J et al. Residual OCTN2 transporter activity, carnitine levels and symptoms correlate in patients with primary carnitine deficiency. MGM Reports. 2014 Apr; 1:241-248. Rose EC et al. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012 Jan;33(1):118-23. Schimmenti LA et al. Expanded newborn screening identifies maternal primary carnitine deficiency. Mol Genet Metab. 2007 Apr;90(4):441-5.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000186152	SCV000609515	likely pathogenic	not provided	2017-05-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000173299	SCV000611319	pathogenic	Renal carnitine transport defect	2022-04-28	criteria provided, single submitter	clinical testing
Invitae	RCV000173299	SCV000632526	pathogenic	Renal carnitine transport defect	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the SLC22A5 protein (p.Pro46Ser). This variant is present in population databases (rs202088921, gnomAD 0.08%). This missense change has been observed in individuals with primary carnitine deficiency (PMID: 17126586, 20027113, 20574985, 23430798, 23430858, 23963628). ClinVar contains an entry for this variant (Variation ID: 193250). 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: 17126586, 21126579). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173299	SCV000698144	pathogenic	Renal carnitine transport defect	2017-03-31	criteria provided, single submitter	clinical testing	Variant summary: The SLC22A5 c.136C>T (p.Pro46Ser) variant located in an extracellular loop close to putative glycosylation sites (Filippo_2011) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. These in silico predictions are confirmed via multiple functional studies, Rose_2012 and Filipp_2011, that indicate the variant to "impair glycosylation and maturation of OCTN2 transporters to the plasma membrane." The variant of interest was observed in 55/99736 control chromosomes at a frequency of 0.0005515, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC22A5 variant (0.0045644). Multiple publications have cited the variant in both asymptomatic mothers and symptomatic patients, although indicated to have a mild phenotype (easy fatigability, muscle pain with exercise, fasting tolerance). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000173299	SCV000711452	pathogenic	Renal carnitine transport defect	2016-06-06	criteria provided, single submitter	clinical testing	The p.Pro46Ser variant in SLC22A5 has been reported in at least 10 individuals w ith primary carnitine deficiency in the compound heterozygous state (Schimmenti 2007, di San Filippo 2011, Rasmussen 2014). The phenotypic spectrum ranges from easy fatigability, cardiac arrhythmias, and fasting intolerance to asymptomatic adults. This variant has also been identified 0.05% (55/99,736) of chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202088921). In vitro functional studies also provide evidence that the p.Pro4 6Ser variant may impact protein function (di San Filippo 2011). In summary, this variant meets our criteria to be classified as pathogenic for primary carnitine deficiency in an autosomal recessive manner based upon its identification in tr ans with other disease-associated variants in patients and functional impact.
Illumina Laboratory Services, Illumina	RCV000173299	SCV000915111	pathogenic	Renal carnitine transport defect	2018-10-22	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the SLC22A5 c.136C>T (p.Pro46Ser) missense variant has been reported in a total of 33 individuals with systemic primary carnitine deficiency, including in a homozygous state in two, in a compound heterozygous state in 25, and in a heterozygous state in six (Li et al. 2010; Filippo et al. 2011; Rose et al. 2012; De Biase et al. 2012; de Boer et al. 2013; Rasmussen et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00093 in the European (non-Finnish) population of the Exome Aggregation Consortium. When expressed in CHO cells, the p.Pro46Ser variant protein had reduced carnitine transport compared to wild type and was largely retained in the cytoplasm rather than being found at the plasma membrane (Filippo et al. 2011). Consistent with the residual transport activity, the variant appears to be associated with a milder phenotype and is commonly found in asymptomatic individuals; at least 11 of the 25 compound heterozygous probands reported here were asymptomatic. Based on the collective evidence, the p.Pro46Ser variant is classified as pathogenic for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000173299	SCV001162973	pathogenic	Renal carnitine transport defect		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000173299	SCV001193788	likely pathogenic	Renal carnitine transport defect	2019-12-17	criteria provided, single submitter	clinical testing	NM_003060.3(SLC22A5):c.136C>T(P46S) is classified as likely pathogenic in the context of primary carnitine deficiency and may be associated with a mild form of this disease. Sources cited for classification include the following: PMID 17126586, 21126579, 20574985, 21922592, 23430798 and 23653224. Classification of NM_003060.3(SLC22A5):c.136C>T(P46S) 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	RCV000186152	SCV001247706	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000173299	SCV002020648	pathogenic	Renal carnitine transport defect	2021-09-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV001810432	SCV002047382	pathogenic	Axial hypotonia	2021-12-13	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP2,PP3,PP5
Genome-Nilou Lab	RCV000173299	SCV002055792	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000173299	SCV002556790	likely pathogenic	Renal carnitine transport defect	2021-07-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000173299	SCV002557797	pathogenic	Renal carnitine transport defect	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary systemic carnitine deficiency (MIM#212140). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The same variant has been found in asymptomatic or minimally symptomatic adult women and in a compound heterozygous mother with cardiac arrest (PMID: 28841266). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (70 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most frequent mutations identified in individuals with primary systemic carnitine deficiency (ClinVar, PMID: 17126586, 22989098, 28841266). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Giacomini Lab, University of California, San Francisco	RCV000173299	SCV002576643	pathogenic	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000186152	SCV004226135	pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing	PP3, PM3, PM5, PS3, PS4_moderate
Institute of Immunology and Genetics Kaiserslautern	RCV000173299	SCV004363621	pathogenic	Renal carnitine transport defect	2024-02-02	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PM2, PM5, PP3, PP5; Variant was found in heterozygous state
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000186152	SCV001740811	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000186152	SCV001930060	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000186152	SCV001954236	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000186152	SCV001973774	likely pathogenic	not provided		no assertion criteria provided	clinical testing