NM_003060.4(SLC22A5):c.-149G>A AND Renal carnitine transport defect

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Mar 30, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000022286.27

Allele description [Variation Report for NM_003060.4(SLC22A5):c.-149G>A]

NM_003060.4(SLC22A5):c.-149G>A

Genes:

LOC129994569:ATAC-STARR-seq lymphoblastoid silent region 16317 [Gene]
MIR3936HG:MIR3936 host gene [Gene - HGNC]
SLC22A5:solute carrier family 22 member 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.1

Genomic location:

Preferred name:

NM_003060.4(SLC22A5):c.-149G>A

HGVS:

NC_000005.10:g.132369824G>A
NG_008982.2:g.5121G>A
NG_174015.1:g.332G>A
NM_001308122.2:c.-149G>A
NM_003060.4:c.-149G>AMANE SELECT
NC_000005.9:g.131705516G>A
NM_003060.3:c.-149G>A

Nucleotide change:

-149G-A

Links:

OMIM: 603377.0023; dbSNP: rs57262206

NCBI 1000 Genomes Browser:

rs57262206

Molecular consequence:

NM_001308122.2:c.-149G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_003060.4:c.-149G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]

Condition(s)

Name:: Renal carnitine transport defect (CDSP)
Synonyms:: CARNITINE TRANSPORTER, PLASMA-MEMBRANE, DEFICIENCY OF; Primary carnitine deficiency; Carnitine uptake defect; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008919; MedGen: C0342788; Orphanet: 158; OMIM: 212140

Recent activity

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PREDICTED: Vicugna pacos ALG2 alpha-1,3/1,6-mannosyltransferase (ALG2), transcri...
PREDICTED: Vicugna pacos ALG2 alpha-1,3/1,6-mannosyltransferase (ALG2), transcript variant X10, mRNA
gi|1777466522|ref|XM_031677357.1|

Nucleotide
cytochrome oxidase subunit 1, partial (mitochondrion) [Leptacis sp. BOLD:AAU8358...
cytochrome oxidase subunit 1, partial (mitochondrion) [Leptacis sp. BOLD:AAU8358]
gi|930505825|gb|ALF64446.1|

Protein
txid7955[organism] AND (uckl1a[gene symbol] OR (GDQQ01072085 OR G... (18)
txid7955[organism] AND (uckl1a[gene symbol] OR (GDQQ01072085 OR GDQQ01072085.* OR XR_662361 OR XR_662361.* OR XM_017357362 OR XM_017357362.* OR XM_005167050 OR XM_005167050.* OR NM_001128259 OR NM_001128259.*))
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001207654	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31187905, 28492532
SCV001271305	OMIM	no assertion criteria provided	Pathogenic (May 22, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001317128	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV001748741	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31980526, 31187905, 31864849 Citation Link,
SCV002020654	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002055732	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004201266	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.

Hou YC, Yu HC, Martin R, Cirulli ET, Schenker-Ahmed NM, Hicks M, Cohen IV, Jönsson TJ, Heister R, Napier L, Swisher CL, Dominguez S, Tang H, Li W, Perkins BA, Barea J, Rybak C, Smith E, Duchicela K, Doney M, Brar P, Hernandez N, et al.

Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):3053-3062. doi: 10.1073/pnas.1909378117. Epub 2020 Jan 24.

PubMed [citation]

PMID:: 31980526
PMCID:: PMC7022190

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001207654.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV001271305.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

After finding low carnitine in 2 sibs and their maternal first cousin by newborn screening, Verbeeten et al. (2020) found that their mothers, who were sisters, and a maternal uncle had primary carnitine deficiency (CDSP; 212140) with low plasma carnitine and increased fractional excretion of free carnitine in the urine. Next-generation sequencing identified a homozygous c.-149G-A transition (c.-149G-A, NM_003060) in the SLC22A5 gene in the 3 affected individuals and carrier status in the 3 infants. Skin fibroblast studies from the affected male showed deficient carnitine uptake at less than 6% of control values. Verbeeten et al. (2020) also found that the wife of the affected male was a carrier for the mutation and that 2 of their children were homozygous for the mutation and diagnosed with carnitine uptake deficiency.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001317128.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001748741.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020654.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002055732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004201266.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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