Submissions for variant NM_003060.4(SLC22A5):c.424G>T (p.Ala142Ser)

gnomAD frequency: 0.00003  dbSNP: rs151231558

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723414	SCV000111950	pathogenic	not provided	2015-12-30	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000022320	SCV000584113	pathogenic	Renal carnitine transport defect	2013-10-21	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000723414	SCV000605126	pathogenic	not provided	2018-01-31	criteria provided, single submitter	clinical testing
Invitae	RCV000022320	SCV000632550	pathogenic	Renal carnitine transport defect	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 142 of the SLC22A5 protein (p.Ala142Ser). This variant is present in population databases (rs151231558, gnomAD 0.009%). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 20574985, 21922592). 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: 25372). 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 not expected to disrupt SLC22A5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SLC22A5 function (PMID: 2216472, 16652335, 21922592). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022320	SCV000698149	pathogenic	Renal carnitine transport defect	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.424G>T (p.Ala142Ser) results in a conservative amino acid change located in the Major facilitator superfamily domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251494 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.424G>T has been reported in the literature in multiple individuals affected with Systemic Primary Carnitine Deficiency, in most cases with p.R488H in cis, along with a second pathogenic variant on the second allele (Amat di San Filippo_2006, Frigeni_2017, Gallant_2017, Mazzini_2011, Thompson_2018). Two publications, one of which is a large study of 143 patients evaluated for Systemic Primary Carnitine Deficiency, reports this variant (p.A142S) in isolation along with a second pathogenic allele in trans (Li_2010, El-Hattab_2010). A functional study showed that the carnitine transport was markedly impaired when both mutations were combined within the same cDNA, however, none of the two missense mutations impaired carnitine transport when expressed alone in CHO cells (Amat di San Filippo_2006). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=2). Based on this evidence, the variant is classified as pathogenic both in isolation as well as when observed as a complex allele in cis with p.R488H.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000022320	SCV000967639	likely pathogenic	Renal carnitine transport defect	2017-08-07	criteria provided, single submitter	clinical testing	The p.Ala142Ser (NM_003060.3 c.424G>T) variant in SLC22A5 (previously referred t o as OCTN2) has been reported in at least 1 homozygous and 9 compound heterozygo us individuals with primary carnitine deficiency or asymptomatic mothers of pati ents identified in NBS (Amat di San Filippo 2006, Li 2010, Mazzini 2011, Rose 2 012).This variant has been identified in 0.009% (12/126,728) of European chromos omes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.or g; dbSNP rs151231558). Although this variant has been seen in the general popula tion, its frequency is low enough to be consistent with a recessive carrier freq uency. In summary, although additional studies are required to fully establish i ts clinical significance, the p.Ala142Thr variant is likely pathogenic for prima ry carnitine deficiency in an autosomal recessive manner based upon its occurren ce in individuals with this disease.
Genome-Nilou Lab	RCV000022320	SCV002055802	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000022320	SCV002801962	likely pathogenic	Renal carnitine transport defect	2022-04-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022320	SCV004201244	likely pathogenic	Renal carnitine transport defect	2023-10-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000022320	SCV000678028	likely pathogenic	Renal carnitine transport defect	2017-06-12	no assertion criteria provided	clinical testing