Submissions for variant NM_003060.4(SLC22A5):c.1159T>C (p.Tyr387His)

dbSNP: rs2126789736

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002042412	SCV002291040	pathogenic	Renal carnitine transport defect	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 387 of the SLC22A5 protein (p.Tyr387His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SLC22A5-related conditions (PMID: 28711408, 32778825; internal data). 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: 1499745). 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%. This variant disrupts the p.Tyr387 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been observed in individuals with SLC22A5-related conditions (PMID: 33181153), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690223	SCV005185418	uncertain significance	not specified	2024-05-07	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1159T>C (p.Tyr387His) 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 damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1159T>C has been reported in the literature in at least one individual affected with Systemic Primary Carnitine Deficiency (e.g. Gallant_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Systemic Primary Carnitine Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28711408). ClinVar contains an entry for this variant (Variation ID: 1499745). Based on the evidence outlined above, the variant was classified as uncertain significance.