Submissions for variant NM_003060.4(SLC22A5):c.641C>T (p.Ala214Val)

dbSNP: rs386134199

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186137	SCV000239162	likely pathogenic	not provided	2023-07-04	criteria provided, single submitter	clinical testing	Functional studies show inconsistent carnitine transport activity including one study with significantly reduced carnitine transport activity (Rose 2012), one study with 32.56% transport activity (Frigeni et al., 2017) and one study with only a slight decrease in carnitine transport (Toh et al., 2011); 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: 20027113, 21864509, 21922592, 28841266, 28711408, 34178604, 32778825, 21126579, 29659532, 20574985, 27460824, 26659599, 23798014, 29930244, 23430858, 26828774, 36535739, 36343260)
Eurofins Ntd Llc (ga)	RCV000186137	SCV000331244	uncertain significance	not provided	2016-06-22	criteria provided, single submitter	clinical testing
Invitae	RCV000022332	SCV000961614	likely pathogenic	Renal carnitine transport defect	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 214 of the SLC22A5 protein (p.Ala214Val). This variant is present in population databases (rs386134199, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20027113, 28841266; 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: 38279). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SLC22A5 function (PMID: 21864509, 36343260). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000022332	SCV001158626	likely pathogenic	Renal carnitine transport defect	2018-09-07	criteria provided, single submitter	clinical testing	The SLC22A5 c.641C>T; p.Ala214Val variant (rs386134199) has been reported in multiple unrelated individuals with systemic primary carnitine deficiency (PCD) (El-Hattab 2010, Li 2010, Rose 2012, ARUP PCD variant database) and is listed in ClinVar (Variation ID: 38279). Testing at ARUP Laboratories has further identified this variant in both the homozygous state or with another pathogenic variant in multiple individuals with plasma and/or urine carnitine levels consistent with PCD. The p.Ala214Val variant is observed in the South Asian population at an overall frequency of 0.58% in the Genome Aggregation Database (180/30782 alleles, 3 homozygotes). However, its frequency in the general population may be confounded by asymptomatic adult individuals with PCD (Magoulas 2012). The alanine at residue 214 is highly conserved, and computational algorithms (SIFT, PolyPhen) predict that this variant is deleterious. Functional analyses have produced variable results but mostly suggest a mild to moderate defect in p.Ala214Val carnitine transport. While an early report observed wildtype activity of the p.Ala214Val variant in transiently transfected HEK293 cells (Toh 2011), later studies observed <33% of wildtype transport activity in stably transfected CHO cells and 16.2% activity in fibroblasts from a p.Ala214Val homozygous individual (Frigeni 2017, Rose 2012). Based on its presence in clinically affected individuals with biochemical profiles consistent with PCD, the p.Ala214Val variant is considered to be likely pathogenic. References: ARUP PCD variant database: http://www.arup.utah.edu/database/OCTN2/OCTN2_welcome.php El-Hattab A et al. Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects. Genet Med. 2010; 12(1):19-24. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Li FY 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. Magoulas P et al. Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012; 7:68. Rose E et al. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012; 33(1):118-23. Toh D et al. Functional analysis of pharmacogenetic variants of human organic cation/carnitine transporter 2 (hOCTN2) identified in Singaporean populations. Biochem Pharmacol. 2011; 82(11):1692-9.
Baylor Genetics	RCV000022332	SCV001162976	pathogenic	Renal carnitine transport defect		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000022332	SCV002055753	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000022332	SCV002060133	uncertain significance	Renal carnitine transport defect	2021-10-01	criteria provided, single submitter	clinical testing	NM_003060.3(SLC22A5):c.641C>T(A214V) is a missense variant classified as a variant of uncertain significance in the context of primary carnitine deficiency. A214V has been observed in cases with relevant disease (PMID: 28841266, 20574985, 23430858, 21922592, 23798014, 28711408). Functional assessments of this variant are available in the literature (PMID: 21864509, 21922592, 28841266). A214V has been observed in population frequency databases (gnomAD: SAS 0.59%). In summary, there is insufficient evidence to classify NM_003060.3(SLC22A5):c.641C>T(A214V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Mendelics	RCV000022332	SCV002519754	pathogenic	Renal carnitine transport defect	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022332	SCV002555621	likely pathogenic	Renal carnitine transport defect	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.641C>T (p.Ala214Val) results in a non-conservative amino acid change located in the major facilitator superfamily domain (IPR020846) 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 0.00072 in 251492 control chromosomes, predominantly at a frequency of 0.0059 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency phenotype (0.0046), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin .c.641C>T has been reported in the literature in compound heterozygous/homozygous infants identified through newborn metabolic screening, many of whom were born to asymptomatic compound heterozygous/homozygous mothers (El-Hattab_2010, Rose_2012, Frigeni_2017, Schiergens_2021). Cardiac function in these mothers were not evaluated except for one individual who had a history of heart palpitations and sinus tachycardia (El-Hattab_2010). These data indicate that the variant is likely to be associated with disease. Several publications examined the effect of the variant on cellular carnitine transport activity through stable transfection of either HEK-293 cells (Toh_2011) or CHO cells (Rose_2012, Frigeni_2017). In HEK-293 cells, the variant had no effect on carnitine uptake (Toh_2011), but in CHO cells, the variant had 32.56% transport activity (Frigeni_2017). The following publications have been ascertained in the context of this evaluation (PMID: 20027113, 28841266, 36343260, 21922592, 34178604, 21864509). Ten ClinVar submitters have assessed the variant since 2014: Six classified this variant as pathogenic/ likely pathogenic and four as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Giacomini Lab, University of California, San Francisco	RCV000022332	SCV002576676	uncertain significance	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000022332	SCV003823361	uncertain significance	Renal carnitine transport defect	2020-11-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV002226449	SCV002078310	likely pathogenic	Decreased circulating carnitine concentration	2021-05-20	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000022332	SCV002107433	likely pathogenic	Renal carnitine transport defect	2021-05-20	no assertion criteria provided	clinical testing