Submissions for variant NM_003060.4(SLC22A5):c.95A>G (p.Asn32Ser)

gnomAD frequency: 0.00001  dbSNP: rs72552725

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414281	SCV000490803	pathogenic	not provided	2021-08-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate carnitine transport activity was significantly impaired compared to controls (Rose et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 25846890, 12210323, 21922592, 28841266, 31373028, 30219858, 30863740, 28105570, 28170084, 17126586, 23379544, 26828774, no PMID, 25665836, 23653224, 23963628)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506183	SCV000605132	pathogenic	not specified	2016-12-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022302	SCV000698159	pathogenic	Renal carnitine transport defect	2017-05-22	criteria provided, single submitter	clinical testing	Variant summary: The SLC22A5 c.95A>G (p.Asn32Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/112066 control chromosomes at a frequency of 0.0000268, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC22A5 variant (0.0045644). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. Additionally, carnitine uptake studies in cultured skin fibroblasts showed that the mean residual OCTN2 transporter activity was 4% of normal in patients homozygous for this variant (Rasmussen_2014). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000414281	SCV000700441	pathogenic	not provided	2017-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022302	SCV000829202	pathogenic	Renal carnitine transport defect	2024-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 32 of the SLC22A5 protein (p.Asn32Ser). This variant is present in population databases (rs72552725, gnomAD 0.01%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 12210323, 23653224, 23963628, 25665836). ClinVar contains an entry for this variant (Variation ID: 25355). 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) indicates that this missense variant is expected to disrupt SLC22A5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000414281	SCV001245742	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000022302	SCV002020651	pathogenic	Renal carnitine transport defect	2023-05-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000022302	SCV002055791	pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000022302	SCV002802071	pathogenic	Renal carnitine transport defect	2024-04-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022302	SCV004201261	pathogenic	Renal carnitine transport defect	2024-02-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000022302	SCV000788592	pathogenic	Renal carnitine transport defect	2017-05-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000022302	SCV001458681	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000414281	SCV001800772	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000414281	SCV001928024	pathogenic	not provided		no assertion criteria provided	clinical testing