5-132370108-C-T

Variant names:

• chr5-132370108-C-T
• rs202088921
• NM_003060.4:c.136C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_003060.4(SLC22A5):​c.136C>T​(p.Pro46Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,611,858 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (1 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25
• Conservation: PhyloP100: 7.28

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]

MIR3936HG (HGNC:40538): (MIR3936 host gene)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 5-132370108-C-T is Pathogenic according to our data. Variant chr5-132370108-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 193250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132370108-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-132370108-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.136C>T	p.Pro46Ser	missense_variant	Exon 1 of 10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.136C>T	p.Pro46Ser	missense_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000446 AC: 109 AN: 244204 Hom.: 0 AF XY: 0.000413 AC XY: 55 AN XY: 133208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.000605

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000956

Gnomad NFE exome AF: 0.000886

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000791 AC: 1154 AN: 1459644 Hom.: 1 Cov.: 31 AF XY: 0.000724 AC XY: 526 AN XY: 726162

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000997

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152214 Hom.: 1 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74376

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000727 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000454 AC: 55

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:15

Mar 31, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SLC22A5 c.136C>T (p.Pro46Ser) variant located in an extracellular loop close to putative glycosylation sites (Filippo_2011) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. These in silico predictions are confirmed via multiple functional studies, Rose_2012 and Filipp_2011, that indicate the variant to "impair glycosylation and maturation of OCTN2 transporters to the plasma membrane." The variant of interest was observed in 55/99736 control chromosomes at a frequency of 0.0005515, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC22A5 variant (0.0045644). Multiple publications have cited the variant in both asymptomatic mothers and symptomatic patients, although indicated to have a mild phenotype (easy fatigability, muscle pain with exercise, fasting tolerance). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC22A5 c.136C>T; p.Pro46Ser variant (rs202088921) is reported in the literature in a homozygous or compound heterozygous state in multiple individuals with primary carnitine deficiency (de Boer 2013, Filippo 2011, Frigeni 2017, Rasmussen 2014, Schimmenti 2007). Functional analyses of the variant protein show reduced transport to the cell membrane and substantially reduced carnitine transport activity (Filippo 2011, Frigeni 2017, Rose 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 193250), and it is found in the general population at a frequency of 0.04% (118/275568 alleles) in the Genome Aggregation Database. The proline at codon 46 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.899). Based on available information, this variant is considered to be pathogenic. References: de Boer L et al. Primary Carnitine (OCTN2) Deficiency Without Neonatal Carnitine Deficiency. JIMD Rep. 2013;10:39-40. Filippo CA et al. Glycosylation of the OCTN2 carnitine transporter: study of natural mutations identified in patients with primary carnitine deficiency. Biochim Biophys Acta. 2011 Mar;1812(3):312-20. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Rasmussen J et al. Residual OCTN2 transporter activity, carnitine levels and symptoms correlate in patients with primary carnitine deficiency. MGM Reports. 2014 Apr; 1:241-248. Rose EC et al. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012 Jan;33(1):118-23. Schimmenti LA et al. Expanded newborn screening identifies maternal primary carnitine deficiency. Mol Genet Metab. 2007 Apr;90(4):441-5. -

Oct 03, 2022

Giacomini Lab, University of California, San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

- -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the SLC22A5 c.136C>T (p.Pro46Ser) missense variant has been reported in a total of 33 individuals with systemic primary carnitine deficiency, including in a homozygous state in two, in a compound heterozygous state in 25, and in a heterozygous state in six (Li et al. 2010; Filippo et al. 2011; Rose et al. 2012; De Biase et al. 2012; de Boer et al. 2013; Rasmussen et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00093 in the European (non-Finnish) population of the Exome Aggregation Consortium. When expressed in CHO cells, the p.Pro46Ser variant protein had reduced carnitine transport compared to wild type and was largely retained in the cytoplasm rather than being found at the plasma membrane (Filippo et al. 2011). Consistent with the residual transport activity, the variant appears to be associated with a milder phenotype and is commonly found in asymptomatic individuals; at least 11 of the 25 compound heterozygous probands reported here were asymptomatic. Based on the collective evidence, the p.Pro46Ser 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. -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary systemic carnitine deficiency (MIM#212140). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The same variant has been found in asymptomatic or minimally symptomatic adult women and in a compound heterozygous mother with cardiac arrest (PMID: 28841266). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (70 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most frequent mutations identified in individuals with primary systemic carnitine deficiency (ClinVar, PMID: 17126586, 22989098, 28841266). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PS3, PM2, PM5, PP3, PP5; Variant was found in heterozygous state -

Jun 06, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro46Ser variant in SLC22A5 has been reported in at least 10 individuals w ith primary carnitine deficiency in the compound heterozygous state (Schimmenti 2007, di San Filippo 2011, Rasmussen 2014). The phenotypic spectrum ranges from easy fatigability, cardiac arrhythmias, and fasting intolerance to asymptomatic adults. This variant has also been identified 0.05% (55/99,736) of chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202088921). In vitro functional studies also provide evidence that the p.Pro4 6Ser variant may impact protein function (di San Filippo 2011). In summary, this variant meets our criteria to be classified as pathogenic for primary carnitine deficiency in an autosomal recessive manner based upon its identification in tr ans with other disease-associated variants in patients and functional impact. -

Jul 22, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_003060.3(SLC22A5):c.136C>T(P46S) is classified as likely pathogenic in the context of primary carnitine deficiency and may be associated with a mild form of this disease. Sources cited for classification include the following: PMID 17126586, 21126579, 20574985, 21922592, 23430798 and 23653224. Classification of NM_003060.3(SLC22A5):c.136C>T(P46S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the SLC22A5 protein (p.Pro46Ser). This variant is present in population databases (rs202088921, gnomAD 0.08%). This missense change has been observed in individuals with primary carnitine deficiency (PMID: 17126586, 20027113, 20574985, 23430798, 23430858, 23963628). ClinVar contains an entry for this variant (Variation ID: 193250). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 17126586, 21126579). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:9

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 18, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Carnitine transport was significantly decreased in both skin fibroblasts from patients harboring P46S and in CHO cells overexpressing P46S (Frigeni et al., 2017; Rose et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31980526, 30609409, 21126579, 17126586, 29614331, 29111448, 23430858, 27896095, 26828774, 28711408, 28841266, 23653224, 21922592, 20574985, 20027113, 23520115, 22989098, 23430798, 23963628) -

Aug 22, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM3, PM5, PS3, PS4_moderate -

See cases Pathogenic:1

Dec 13, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM1,PM2,PP2,PP3,PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.96
MVP		1.0
MPC		0.81
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs202088921; hg19: chr5-131705800;