NM_003060.4(SLC22A5):c.844C>T (p.Arg282Ter) AND Renal carnitine transport defect

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Mar 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000006785.36

Allele description [Variation Report for NM_003060.4(SLC22A5):c.844C>T (p.Arg282Ter)]

NM_003060.4(SLC22A5):c.844C>T (p.Arg282Ter)

Gene:

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.844C>T (p.Arg282Ter)

HGVS:

NC_000005.10:g.132387044C>T
NG_008982.2:g.22341C>T
NM_001308122.2:c.916C>T
NM_003060.4:c.844C>TMANE SELECT
NP_001295051.1:p.Arg306Ter
NP_003051.1:p.Arg282Ter
NC_000005.9:g.131722736C>T
NM_003060.3:c.844C>T

Protein change:

R282*; ARG282TER

Links:

OMIM: 603377.0008; dbSNP: rs121908886

NCBI 1000 Genomes Browser:

rs121908886

Molecular consequence:

NM_001308122.2:c.916C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003060.4:c.844C>T - nonsense - [Sequence Ontology: SO:0001587]

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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Suttonella indologenes strain ATCC 25869 16S ribosomal RNA, partial sequence
Suttonella indologenes strain ATCC 25869 16S ribosomal RNA, partial sequence
gi|343206092|ref|NR_044681.1|

Nucleotide
MGAT4C [Empidonax traillii]
MGAT4C [Empidonax traillii]
Gene ID:114064493

Gene
PYGB [Tinamus guttatus]
PYGB [Tinamus guttatus]
Gene ID:104570657

Gene
SLC35D3 [Neogale vison]
SLC35D3 [Neogale vison]
Gene ID:122899042

Gene
FADS2 [Numida meleagris]
FADS2 [Numida meleagris]
Gene ID:110400735

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026981	OMIM	no assertion criteria provided	Pathogenic (Aug 2, 1999)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 10051646, 10480371, 10425211
SCV000452735	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21922592, 10480371, 10425211, 10051646, 15714519, 20574985, 23430869 Citation Link,
SCV000632573	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9916797, 10051646, 10425211, 10480371, 21922592, 28492532
SCV000920216	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 27, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15714519, 28841266, 21922592, 10425211, 10051646 Citation Link,
SCV001462813	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001474454	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (May 22, 2020)	germline	clinical testing	Citation Link,
SCV002055816	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]
SCV002811092	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004201289	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 19, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency.

Li FY, El-Hattab AW, Bawle EV, Boles RG, Schmitt ES, Scaglia F, Wong LJ.

Hum Mutat. 2010 Aug;31(8):E1632-51. doi: 10.1002/humu.21311.

PubMed [citation]

PMID:: 20574985

Identification of mutations and evaluation of cardiomyopathy in Turkish patients with primary carnitine deficiency.

Kilic M, Ozgül RK, Coşkun T, Yücel D, Karaca M, Sivri HS, Tokatli A, Sahin M, Karagöz T, Dursun A.

JIMD Rep. 2012;3:17-23. doi: 10.1007/8904_2011_36. Epub 2011 Sep 22.

PubMed [citation]

PMID:: 23430869
PMCID:: PMC3509853

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000026981.4

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

Description

In a patient with primary carnitine deficiency (CDSP; 212140), Wang et al. (1999) found homozygosity for a C-to-T transition in exon 5 of the SLC22A5 gene, converting codon 282 from CGA (arg) to TGA (stop). Both parents were heterozygous for the mutation.

Vaz et al. (1999) found the R282X mutation in homozygous state in a patient with classic manifestations of systemic carnitine deficiency. Reintroduction of wildtype OCTN2 cDNA into fibroblasts of the patient by transient transfection restored the cellular carnitine uptake, confirming that mutation in OCTN2 was the cause of the systemic carnitine deficiency.

Burwinkel et al. (1999) identified the R282X mutation in 2 German patients who had different haplotypes, suggesting that this mutation may either be recurrent or an ancient founder mutation. They also found that R282X was associated with a splicing abnormality at the intron 6/exon 7 junction. However, no mutations were present in exon 6, intron 6, or exon 7, suggesting that defective splicing of exon 7 on the R282X allele was due to an unconventional, long-distance mechanism.

#	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, SCV000452735.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The SLC22A5 c.844C>T (p.Arg282Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg282Ter variant has been reported in at least seven studies in a total of ten individuals with systemic primary carnitine deficiency, including in three in a homozygous state, in three in a compound heterozygous state, and in four in a heterozygous state (Burwinkel et al. 1999; Wang et al. 1999; Vaz et al. 1999; Dobrowolski et al. 2005; Li et al. 2010; Kilic et al. 2012; Rose et al. 2012). The mother of one of the heterozygous patients was also a carrier of the variant but was asymptomatic. Control data are not available for the p.Arg282Ter variant, which is reported at a frequency of 0.00029 in the African population of the Exome Aggregation Consortium. The p.Arg282Ter variant has also been associated with an unconventional splicing defect (Burwinkel et al. 1999). Fibroblasts from one of the homozygous individuals were shown to exhibit absent saturable carnitine transport and 25% of the normal mRNA expression. Functional studies in Chinese hamster ovary cells showed that transfection with the wildtype protein could increase carnitine transport but that expression of the p.Arg282Ter variant protein could not (Wang et al. 1999). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg282Ter 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.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000632573.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Arg282*) in the SLC22A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). This variant is present in population databases (rs121908886, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with primary carnitine deficiency (PMID: 10051646, 10425211, 10480371, 21922592). ClinVar contains an entry for this variant (Variation ID: 6416). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920216.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: SLC22A5 c.844C>T (p.Arg282X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.9e-05 in 121404 control chromosomes (gnomAD). c.844C>T has been reported in the literature in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Wang 1999, Burwinkel 1999, Dobrowolski 2005, Rose 2012). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Wang 1999, Frigeni 2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. 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 Natera, Inc., SCV001462813.1

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

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001474454.1

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

#	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, SCV002055816.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002811092.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004201289.2

#	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 13, 2024

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