Submissions for variant NM_003060.4(SLC22A5):c.394-16T>A

gnomAD frequency: 0.00001  dbSNP: rs775097754

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558301	SCV000632548	pathogenic	Renal carnitine transport defect	2024-07-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the SLC22A5 gene. It does not directly change the encoded amino acid sequence of the SLC22A5 protein. This variant is present in population databases (rs775097754, gnomAD 0.02%). This variant has been observed in individual(s) with primary carnitine deficiency (PMID: 21922592). 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: 460407). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000558301	SCV000799118	uncertain significance	Renal carnitine transport defect	2018-04-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091582	SCV001247710	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	SLC22A5: PM2, PM3, PP4:Moderate, PS3:Supporting, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000558301	SCV001432006	likely pathogenic	Renal carnitine transport defect	2021-10-21	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.394-16T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251494 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (4e-05 vs 0.0046), allowing no conclusion about variant significance. c.394-16T>A has been reported in the literature in at-least one asymptomatic woman in a study evaluating asymptomatic mothers with primary carnitine deficiency identified by low carnitine levels in their infant by newborn screening (Rose_2012) and one comprehensively genotyped individual affected with Systemic Primary Carnitine Deficiency (Frigeni_2017) and subsequently cited by others (Longo_2016). The affected individual reported by Frigeni_2017 harbored a pathogenic variant on the second allele and had a significantly reduced carnitine transport activity in fibroblasts. Additionally, the variant has also been observed in two individuals with reduced serum/plasma carnitine levels, one heterozygous (Schiergens_2021) and one compound heterozygous for this variant along with another pathogenic variant (Maguolo_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001091582	SCV001825935	uncertain significance	not provided	2021-06-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 28841266, 32793418, 34178604, 27535533, 26828774, 21922592)
Genome-Nilou Lab	RCV000558301	SCV002055743	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000558301	SCV004201308	likely pathogenic	Renal carnitine transport defect	2024-03-25	criteria provided, single submitter	clinical testing