chr5-132385370-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_003060.4(SLC22A5):c.695C>T(p.Thr232Met) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
SLC22A5
NM_003060.4 missense
NM_003060.4 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 5.68
Genes affected
SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-132385370-C-T is Pathogenic according to our data. Variant chr5-132385370-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132385370-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.695C>T | p.Thr232Met | missense_variant | 4/10 | ENST00000245407.8 | NP_003051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.695C>T | p.Thr232Met | missense_variant | 4/10 | 1 | NM_003060.4 | ENSP00000245407.3 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251486Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135918
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GnomAD4 exome AF: 0.000131 AC: 191AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91AN XY: 727170
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GnomAD4 genome AF: 0.000184 AC: 28AN: 152352Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74506
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Renal carnitine transport defect Pathogenic:11Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 09, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Oct 09, 2018 | [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]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 28, 2016 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 16, 2018 | 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. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 04, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | 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. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2024 | Published functional studies found that T232M is associated with significantly impaired carnitine transport (PMID: 16652335, 15714519, 21922592); 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: 16652335, 20981092, 16602102, 34863234, 34704412, 32371215, 33560599, 33757571, 33181153, 31980526, 32371413, 23520115, 15714519, 20574985, 21922592, 20027113, 25087612, 22995991, 28841266, 28711408, 29614331, 29750726, 32778825, 37498360, 38187300, 35314707) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 25, 2023 | PM3_very_strong, PS3_moderate - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at