chr5-132369824-G-A

Variant names:

• chr5-132369824-G-A
• rs57262206
• NM_003060.4:c.-149G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS1_Supporting

The NM_003060.4(SLC22A5):​c.-149G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 988,154 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (10 hom.)
• Consequence: SLC22A5 NM_003060.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 0.368
• Publications: 12 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: Likely_pathogenic. The variant received 6 ACMG points.

• PP5: Variant 5-132369824-G-A is Pathogenic according to our data. Variant chr5-132369824-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 25340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00289 (2414/835880) while in subpopulation NFE AF = 0.00356 (2252/632260). AF 95% confidence interval is 0.00344. There are 10 homozygotes in GnomAdExome4. There are 1166 alleles in the male GnomAdExome4 subpopulation. Median coverage is 11. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.-149G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	ENST00000245407.8	NP_003051.1
SLC22A5	NM_003060.4	c.-149G>A		5_prime_UTR_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.-149G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3
SLC22A5	ENST00000245407.8	c.-149G>A		5_prime_UTR_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152164 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00289 AC: 2414 AN: 835880 Hom.: 10 Cov.: 11 AF XY: 0.00277 AC XY: 1166 AN XY: 420334

African (AFR) AF: 0.000419 AC: 7 AN: 16714

American (AMR) AF: 0.000712 AC: 12 AN: 16862

Ashkenazi Jewish (ASJ) AF: 0.000721 AC: 11 AN: 15258

East Asian (EAS) AF: 0.00 AC: 0 AN: 30774

South Asian (SAS) AF: 0.0000191 AC: 1 AN: 52250

European-Finnish (FIN) AF: 0.00153 AC: 47 AN: 30804

Middle Eastern (MID) AF: 0.000368 AC: 1 AN: 2714

European-Non Finnish (NFE) AF: 0.00356 AC: 2252 AN: 632260

Other (OTH) AF: 0.00217 AC: 83 AN: 38244

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152274 Hom.: 1 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74464

African (AFR) AF: 0.000505 AC: 21 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 67996

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00158

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:9

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-149G>A variant in the SLC22A5 gene has been previously reported in the homozygous or compound heterozygous state in >40 individuals with features of primary carnitine deficiency (Ferdinandusse et al., 2019). This variant also segregated with disease in several affected individuals from one family (Verbeeten et al., 2020). This variant has been described in association with a milder phenotype (Ferdinandusse et al., 2019). This variant has been identified in 171/68,006 European non-Finnish chromosomes (215/152,164 chromosomes overall), including 1 homozygous occurrence, by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: VCV000025340.46). This variant occurs within the 5’ untranslated region (UTR) of SLC22A5. Functional studies demonstrated that this variant introduces a functional upstream out-of-frame translation initiation codon, which suppresses translation from the wild-type initiation codon and results in reduced protein levels and reduced carnitine transporter activity (Ferdinandusse et al., 2019). -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the SLC22A5 gene. It does not change the encoded amino acid sequence of the SLC22A5 protein. This variant is present in population databases (rs57262206, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with primary carnitine deficiency (PMID: 31187905). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 25340). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC22A5 function (PMID: 31187905). For these reasons, this variant has been classified as Pathogenic. -

Aug 02, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC22A5 c.-149G>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0014 in 150938 control chromosomes in the gnomAD v3.1.2 database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.0014 vs 0.0046), allowing no conclusion about variant significance. c.-149G>A has been reported to segregate with carnitine uptake defect in a large family where several affected members were homozygous for the variant of interest (Verbeeten_2020). The variant has also been reported in several other unrelated individuals (homozygous, compound heterozygous and heterozygous) affected with primary carnitine deficiency (Ferdinandusse_2019). Most of the affected patients showed a mild phenotype. Functional studies conducted in patient derived fibroblasts (from homozygous individuals) showed reduced Carnitine transport activity (Verbeeten_2020, Ferdinandusse_2019). Ferdinandusse et al also report that c.-149G>A introduces a functional upstream out-of-frame translation initiation codon and this codon suppresses translation from the wild-type AUG of SLC22A5, resulting in reduced OCTN2 protein levels and therefore, lower OCTN2 transport activity and carnitine deficiency in patients harboring this variant (Ferdinandusse_2019). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 22, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC22A5: PM3:Very Strong, PP1:Moderate, PS3:Moderate, PM2:Supporting -

Dec 08, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the homozygous state and in the presence of a second pathogenic variant in individuals with primary carnitine deficiency (Ferdinandusse et al., 2019); Individuals homozygous for this variant had approximately 31% average carnitine transport activity in fibroblasts compared to controls (Ferdinandusse et al., 2019); In vitro functional studies demonstrate that c.-149G>A introduces an upstream out-of-frame translation initiation codon that causes reduced production of OCTN2 protein (Ferdinandusse et al., 2019); This variant is associated with the following publications: (PMID: 31187905, 31864849, 31980526) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PS3, PS4 -

Inborn genetic diseases Pathogenic:1

Sep 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-149G>A alteration is located in the 5' untranslated region (5'UTR) of the SLC22A5 gene. This alteration consists of a G to A substitution 149 nucleotides upstream from the first translated codon. Based on data from gnomAD, the A allele has an overall frequency of 0.128% (40/31306) total alleles studied. The highest observed frequency was 0.238% (2/842) of Latino alleles. This variant has been identified in the homozygous state and in conjunction with other SLC22A5 variants in individuals with features consistent with systemic primary carnitine deficiency and segregated with disease in at least one family (Ferdinandusse, 2019; Verbeeten, 2020; Ziats, 2021). Functional studies indicated that the variant introduces a functional upstream outofframe translation initiation codon, which suppresses translation from the wildtype ATG of SLC22A5, resulting in lower transport activity. Based on the available evidence, this alteration is classified as pathogenic. -

SLC22A5-related disorder Pathogenic:1

Jul 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC22A5 c.-149G>A variant is located in the 5' untranslated region. This variant has been reported, in the homozygous or compound heterozygous state, in numerous individuals with primary carnitine deficiency (PCD) (Ferdinandusse et al. 2019. PubMed ID: 31187905; Verbeeten et al. 2020. PubMed ID: 31864849). It was found in in the homozygous and apparently compound heterozogous state in several individuals who were classified as having a likely benign form of PCD who were asymptomatic or only had mild symptoms, regardless of treatment. (Crefcoeur et al. 2023. PubMed ID: 37487700). The c.-149G>A variant was predicted to create a novel translation initiation codon upstream of the canonical AUG start codon, and in a functional assay using a luciferase reporter construct, the c.-149G>A variant was found to reduce luciferase activity to 11% of control (Ferdinandusse et al. 2019. PubMed ID: 31187905). Furthermore, carnitine transport activity was reduced in patient fibroblasts with the c.-149G>A variant (Ferdinandusse et al. 2019. PubMed ID: 31187905; Verbeeten et al. 2020. PubMed ID: 31864849). Based on these observations, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.0
DANN	Benign	0.93
PhyloP100		0.37
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=111/189	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: rs57262206; hg19: chr5-131705516;