Submissions for variant NM_003060.4(SLC22A5):c.695C>T (p.Thr232Met)

gnomAD frequency: 0.00018  dbSNP: rs114269482

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000438010	SCV000111953	pathogenic	not provided	2016-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000438010	SCV000514638	pathogenic	not provided	2023-02-20	criteria provided, single submitter	clinical testing	Published functional studies found that T232M is associated with significantly impaired carnitine transport (Amat di San Filippo et al., 2006; Dobrowolski et al., 2005; Rose et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20981092, 16602102, 34863234, 34704412, 32371215, 33560599, 33757571, 33181153, 31980526, 32371413, 16652335, 23520115, 15714519, 20027113, 21922592, 25087612, 22995991, 20574985, 28841266, 28711408, 29614331, 29750726, 32778825)
Invitae	RCV000022339	SCV000632566	pathogenic	Renal carnitine transport defect	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 232 of the SLC22A5 protein (p.Thr232Met). This variant is present in population databases (rs114269482, gnomAD 0.02%). This missense change has been observed in individuals with primary carnitine deficiency (PMID: 15714519, 20574985, 23520115; Invitae). ClinVar contains an entry for this variant (Variation ID: 25386). 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 95%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 15714519, 21922592). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022339	SCV000698153	pathogenic	Renal carnitine transport defect	2016-03-28	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and polar Threonine (T) with a medium size and hydrophobic Methionine (M). 4/4 in silico tools predicts the variant to be disease causing. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0131% which does not exceed the maximal expected allele frequency of a disease causing SLC22A5 variant (0.45%) to exclude pathogenicity. The variant was reported in CDSP patients in compound heterozygosity with other pathogenic variant. Patients with the variant presented with low carnitine levels, easy fatigability, with fatigability during pregnancy indicating a disease causing impact. Furthermore, a functional study demonstrated the variant to reduce carnitine transport compared to the wild-type protein when stably transfected into CHO cells, supporting its causative role in primary carnitine deficiency. Additionally, a clinical diagnostic laboratory classifies variant as Pathogenic. Considering all evidence, the variant was classified as a Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000022339	SCV000886119	pathogenic	Renal carnitine transport defect	2018-11-16	criteria provided, single submitter	clinical testing	The SLC22A5 c.695C>T; p.Thr232Met variant (rs114269482) has been described in the compound heterozygous state individuals with primary carnitine deficiency (Amat di San Filippo 2006, Dobrowolski 2005, Li 2010). It is reported as pathogenic in ClinVar (Variation ID: 25386), and is observed in the general population at an overall frequency of 0.01% (28/282898 alleles) in the Genome Aggregation Database. The threonine at codon 232 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, in vitro functional studies of the variant protein demonstrate impaired carnitine transport (Amat di San Filippo 2006, Dobrowolski 2005). Based on available information, this variant is considered pathogenic. REFERENCES Amat di San Filippo C et al. Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat. 2006 Jun;27(6):513-23. Dobrowolski SF et al. Validation of dye-binding/high-resolution thermal denaturation for the identification of mutations in the SLC22A5 gene. Hum Mutat. 2005 Mar;25(3):306-13. Li F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010 Aug;31(8):E1632-51.
Fulgent Genetics, Fulgent Genetics	RCV000022339	SCV000893684	pathogenic	Renal carnitine transport defect	2022-04-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000022339	SCV000915112	pathogenic	Renal carnitine transport defect	2017-04-28	criteria provided, single submitter	clinical testing	The SLC22A5 c.695C>T (p.Thr232Met) missense variant has been reported in five studies and is found in a total of 12 patients with systemic primary carnitine deficiency, including in nine patients in a compound heterozygous state, in one in a heterozygous state, and in two patients with unknown zygosity (Dobrowolski et al. 2005; Li et al. 2010; El-Hattab et al. 2010; Rose et al. 2012; Chen et al. 2013). The phenotype of this condition is known to be variable and some affected individuals remain asymptomatic despite deficiency of carnitine transport. The 12 patients included two mothers who were tested due to abnormal newborn screening results in their infants (El-Hattab et al. 2010; Rose et al. 2012). Control data are unavailable for the p.Thr232Met variant, which is reported at a frequency of 0.0006 in the All population of the 1000 Genomes Project. Fibroblasts derived from patients with the p.Thr232Met variant showed defective carnitine transport (Dobrowolski et al. 2005). Further, CHO cells transfected with the p.Thr232Met variant had reduced carnitine transport activity (Dobrowolski et al. 2005). Based on the evidence, the p.Thr232Met variant is classified as pathogenic for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000022339	SCV001423614	pathogenic	Renal carnitine transport defect	2018-10-09	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS3, PM_PS4, PM2, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Revvity Omics, Revvity	RCV000022339	SCV002020650	pathogenic	Renal carnitine transport defect	2023-11-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000022339	SCV002055812	likely pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022339	SCV004201263	pathogenic	Renal carnitine transport defect	2023-10-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000438010	SCV004226775	pathogenic	not provided	2023-04-25	criteria provided, single submitter	clinical testing	PM3_very_strong, PS3_moderate
Counsyl	RCV000022339	SCV001132490	likely pathogenic	Renal carnitine transport defect	2019-06-04	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000022339	SCV001462807	pathogenic	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000022339	SCV001749806	not provided	Renal carnitine transport defect		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-04-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.