Submissions for variant NM_003060.4(SLC22A5):c.1409C>T (p.Ser470Phe)

gnomAD frequency: 0.00001  dbSNP: rs386134222

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513827	SCV000610106	pathogenic	not provided	2017-06-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000022381	SCV000799728	uncertain significance	Renal carnitine transport defect	2018-05-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513827	SCV001247715	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022381	SCV001416144	pathogenic	Renal carnitine transport defect	2023-08-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266). 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. ClinVar contains an entry for this variant (Variation ID: 25425). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 12210323). This variant is present in population databases (rs386134222, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 470 of the SLC22A5 protein (p.Ser470Phe).
Centogene AG - the Rare Disease Company	RCV000022381	SCV001424486	pathogenic	Renal carnitine transport defect		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000022381	SCV002055779	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000022381	SCV002576583	likely pathogenic	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Baylor Genetics	RCV000022381	SCV004203600	likely pathogenic	Renal carnitine transport defect	2022-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022381	SCV005185754	pathogenic	Renal carnitine transport defect	2024-05-15	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1409C>T (p.Ser470Phe) 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 8e-06 in 251466 control chromosomes. c.1409C>T has been reported in the literature in the homozygous state in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Cheema_2020, ALghamdi_2018, Lamhonwah_2002). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in CHO cells reports experimental evidence that this variant results in 0 transport activity compared to wildtype (e.g. Frigeni_2017). This variant is also known as c.1481C>T(p.Ser494Phe). The following publications have been ascertained in the context of this evaluation (PMID: 30069296, 33083013, 28841266, 12210323). ClinVar contains an entry for this variant (Variation ID: 25425). Based on the evidence outlined above, the variant was classified as pathogenic.