Submissions for variant NM_003060.4(SLC22A5):c.949G>A (p.Glu317Lys)

gnomAD frequency: 0.00001  dbSNP: rs774792831

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271888	SCV002556076	uncertain significance	not specified	2022-06-22	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.949G>A (p.Glu317Lys) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a cryptic 5' donor site and one predicts the variant strengthens a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.949G>A has been reported in the literature in at least one individual affected with Cardiomyopathy (Amat di San Filippo_2008), which does not provide unequivocal conclusions about association of the variant with Systemic Primary Carnitine Deficiency. Amat di San Filippo_2008 also demonstrated that when expressed in CHO cells, the variant significantly increased carnitine transport rates above what was seen with wild-type. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003096123	SCV003246051	uncertain significance	Renal carnitine transport defect	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 317 of the SLC22A5 protein (p.Glu317Lys). This variant is present in population databases (rs774792831, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 18337137). ClinVar contains an entry for this variant (Variation ID: 1698611). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC22A5 protein function. Experimental studies have shown that this missense change does not substantially affect SLC22A5 function (PMID: 18337137, 28841266). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.