Submissions for variant NM_003060.4(SLC22A5):c.652+1G>A

gnomAD frequency: 0.00001  dbSNP: rs386134200

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000022334	SCV000632561	pathogenic	Renal carnitine transport defect	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the SLC22A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). This variant is present in population databases (rs386134200, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with primary carnitine deficiency (PMID: 12210323). ClinVar contains an entry for this variant (Variation ID: 25381). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects SLC22A5 function (PMID: 2235122, 12210323). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000022334	SCV000893683	pathogenic	Renal carnitine transport defect	2022-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022334	SCV001363922	pathogenic	Renal carnitine transport defect	2019-06-06	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.652+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing 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 251494 control chromosomes (gnomAD). c.652+1G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Lamhonwah_2002, Hwu_2007, Frigeni_2017). These data indicate that the variant may be associated with disease. Two compound heterozygote patients were found to have significantly lower carnitine uptake/levels (Lamhonwah_2002, Hwu_2007). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000022334	SCV002055808	pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022334	SCV003835330	pathogenic	Renal carnitine transport defect	2022-07-25	criteria provided, single submitter	clinical testing
GeneDx	RCV003329234	SCV004036815	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26828774, 28841266, 16602102, 17703373, 12210323)
Natera, Inc.	RCV002226445	SCV002078311	pathogenic	Decreased circulating carnitine concentration	2021-03-31	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000022334	SCV002107434	pathogenic	Renal carnitine transport defect	2021-03-31	no assertion criteria provided	clinical testing