5-132369824-G-A

Position:

• chr5-132369824-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

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:13
• Conservation: PhyloP100: 0.368

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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. Variant chr5-132369824-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.-149G>A		5_prime_UTR_premature_start_codon_gain_variant	1/10	ENST00000245407.8	NP_003051.1
SLC22A5	NM_003060.4	c.-149G>A		5_prime_UTR_variant	1/10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407	c.-149G>A		5_prime_UTR_premature_start_codon_gain_variant	1/10	1	NM_003060.4	ENSP00000245407.3
SLC22A5	ENST00000245407	c.-149G>A		5_prime_UTR_variant	1/10	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

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000712

Gnomad4 ASJ exome AF: 0.000721

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000191

Gnomad4 FIN exome AF: 0.00153

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00217

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

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00158

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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 protein 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 22, 2020	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 20, 2024	PP1_strong, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SLC22A5: PM3:Very Strong, PP1:Moderate, PS3:Moderate, PM2:Supporting -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2024

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2024

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs57262206; hg19: chr5-131705516;