rs139203363

Variant names:

• chr5-132370006-G-A
• rs139203363
• NM_003060.4:c.34G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-132370006-G-A
• chr5-132370006-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1 PM5 PP5 BS2

The NM_003060.4(SLC22A5):​c.34G>A​(p.Gly12Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000844 in 1,613,304 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (3 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:14 O:1
• Conservation: PhyloP100: 5.19
• Publications: 13 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_003060.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132370006-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2766648.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 5-132370006-G-A is Pathogenic according to our data. Variant chr5-132370006-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25349.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.34G>A	p.Gly12Ser	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.34G>A	p.Gly12Ser	missense_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000711 AC: 177 AN: 249114 AF XY: 0.000791

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000933

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000865 AC: 1264 AN: 1460992 Hom.: 3 Cov.: 31 AF XY: 0.000812 AC XY: 590 AN XY: 726862

African (AFR) AF: 0.000239 AC: 8 AN: 33446

American (AMR) AF: 0.000761 AC: 34 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00104 AC: 55 AN: 53002

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00100 AC: 1112 AN: 1111696

Other (OTH) AF: 0.000878 AC: 53 AN: 60356

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74478

African (AFR) AF: 0.000265 AC: 11 AN: 41576

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:14 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Renal carnitine transport defect Pathogenic:4 Uncertain:11 Other:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jun 11, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Oct 03, 2022

Giacomini Lab, University of California, San Francisco

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

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Jul 21, 2017

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Nov 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC22A5 c.34G>A; p.Gly12Ser variant (rs139203363) is reported in the literature in an individual with plasma carnitine deficiency affected with sudden infant death syndrome-like episode (Li 2010) and in two individuals who exhibited sudden unexpected death in infancy (Hertz 2016, Neubauer 2017). This variant is reported as a variant of uncertain significance in ClinVar (Variation ID: 25349).This variant is found in the general population with an overall allele frequency of 0.07% (195/280474 alleles, including one homozygote) in the Genome Aggregation Database. The glycine at codon 12 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, this variant exhibited 51.7% of normal carnitine transport activity in functional assays, and it is unclear if this decrease is sufficient to cause disease (Frigeni 2017). Due to limited information, the clinical significance of the p.Gly12Ser variant is uncertain at this time. References: Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 38:1684-1699. Hertz CL et al. Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. Eur J Hum Genet. 2016 24:817-822. Li FY et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010 31:E1632-1651. Neubauer J et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017 25:404-409. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Sep 01, 2024

Department of Genetics of Metabolic Diseases, Institute of Medical & Molecular Genetics, Hospital Universitario Hospital La Paz

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant NM_003060.3:c.34G>A p.(Gly12Ser) is present at low frequency in gnomAD (0.06953%) and one homozygote has been reported in control populations. Computational prediction tools support a deleterious effect on the gene and functional studies in CHO cells confirm this variant halves OCTN2´s activity (PMID:28841266). This variant has been observed in an individual with abnormal levels of free carnitine consistent with primary carnitine deficiency, carrying this variant along with a second variant of unknown significance (PMID: Hidalgo Mayoral I et al., in press). -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the SLC22A5 protein (p.Gly12Ser). This variant is present in population databases (rs139203363, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20574985, 28841266; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25349). 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%. For these reasons, this variant has been classified as Pathogenic. -

Mar 11, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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May 15, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC22A5 c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00071 in 249114 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00071 vs 0.0046), allowing no conclusion about variant significance. c.34G>A has been observed in individual(s) affected with Systemic Primary Carnitine Deficiency (Jakoby_2021, internal data). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Frigeni_2017, Koleske_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34440436, 28841266, 26350513, 37510298, 34032155, 36343260, 35888728, 20574985, 34637945). ClinVar contains an entry for this variant (Variation ID: 25349). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

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 VUS-3A. The 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. Nonsense and frameshift variants are typically associated with lower carnitine transport and more commonly identified in symptomatic individuals while missense variants and in-frame deletions are typically associated with residual carnitine transport activity and more commonly identified in asymptomatic individuals (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (195 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and moderately conserved with a minor amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS and pathogenic by multiple clinical diagnostic laboratories (ClinVar). This variant has been reported as compound heterozygous with a SLC22A5 nonsense variant in one adult female with primary carnitine deficiency and has also been identified in one individual with sudden unexpected death in infancy who was also found to carry one RYR2 and one AKAP9 variant (PMIDs: 34032155, 26350513). Additionally, it has been reported as a heterozygous VUS in a sudden infant death syndrome case and a heterozygous pathogenic variant in an individual with primary carnitine deficiency (PMIDs: 28074886, 34637945). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into CHO cells demonstrated 51.7% carnitine transport activity compared to WT (PMID: 28841266). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, it should be noted that the p.(Gly12Asp) variant which has a higher Grantham score has been classified as a VUS in ClinVar. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Uncertain:2

Sep 22, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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Jul 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM3 -

Decreased circulating carnitine concentration Uncertain:1

Mar 01, 2024

Lildballe Lab, Aarhus University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

PM1 (m) PP2(sup) PM2(sup) PP3(sup) PP5(noinf) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.0	H;H
PhyloP100		5.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.51
MVP		0.99
MPC		0.80
ClinPred		0.50	D
GERP RS		5.0
PromoterAI		-0.021	Neutral
Varity_R		0.92
gMVP		0.95
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs139203363; hg19: chr5-131705698;