chr5-132385370-C-T

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

Scores

7
9
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 5.68
Variant links:
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
SLC22A5NM_003060.4 linkuse as main transcriptc.695C>T p.Thr232Met missense_variant 4/10 ENST00000245407.8 NP_003051.1 O76082-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC22A5ENST00000245407.8 linkuse as main transcriptc.695C>T p.Thr232Met missense_variant 4/101 NM_003060.4 ENSP00000245407.3 O76082-1

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000915
AC:
23
AN:
251486
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000967
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000131
AC:
191
AN:
1461700
Hom.:
0
Cov.:
31
AF XY:
0.000125
AC XY:
91
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000152
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152352
Hom.:
0
Cov.:
32
AF XY:
0.000201
AC XY:
15
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.000240
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000185
Hom.:
0
Bravo
AF:
0.000170
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000132
AC:
16
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

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 providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 26, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
not provided, no classification providedphenotyping onlyGenomeConnect - 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 submitterclinical testingRevvity Omics, RevvityNov 09, 2023- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 15, 2022- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017The 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 submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalOct 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 28, 2016Variant 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 16, 2018The 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 providedclinical testingCounsylJun 04, 2019- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024This 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 submitterclinical testingEurofins Ntd Llc (ga)Feb 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 10, 2024Published 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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicApr 25, 2023PM3_very_strong, PS3_moderate -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.56
D;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Benign
0.082
D
MetaRNN
Uncertain
0.69
D;D;D
MetaSVM
Uncertain
0.067
D
MutationAssessor
Uncertain
2.3
M;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.043
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.65
MVP
0.96
MPC
0.32
ClinPred
0.34
T
GERP RS
5.9
Varity_R
0.68
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.27
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.27
Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs114269482; hg19: chr5-131721062; API