Submissions for variant NM_003060.4(SLC22A5):c.629A>G (p.Asn210Ser)

gnomAD frequency: 0.00001  dbSNP: rs386134198

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022330	SCV000632560	likely pathogenic	Renal carnitine transport defect	2024-01-22	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 210 of the SLC22A5 protein (p.Asn210Ser). This variant is present in population databases (rs386134198, gnomAD 0.004%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 23798014, 26828774, 28841266; Invitae). ClinVar contains an entry for this variant (Variation ID: 38276). 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 80%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 27931018, 28841266). 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.
GeneDx	RCV001564243	SCV001787378	likely pathogenic	not provided	2021-01-21	criteria provided, single submitter	clinical testing	Expression studies found that this variant is associated with 0.13 residual transport activity compared to wild-type (Frigeni et al., 2017); 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: 28841266, 26828774, 27931018)
Genome-Nilou Lab	RCV000022330	SCV002055752	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000022330	SCV002576674	pathogenic	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022330	SCV003800928	likely pathogenic	Renal carnitine transport defect	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.629A>G (p.Asn210Ser) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251496 control chromosomes (gnomAD). c.629A>G has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (e.g. Waisbren_2013, Frigeni_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating the variant has 0.13% carnitine transport activity when stably expressed in CHO cells as compared to wild type (Frigeni_2017). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000022330	SCV004201269	likely pathogenic	Renal carnitine transport defect	2023-10-08	criteria provided, single submitter	clinical testing