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NM_003060.4(SLC22A5):c.791C>G (p.Thr264Arg) AND Renal carnitine transport defect

Germline classification:
Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:
Mar 31, 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:
RCV000526996.17

Allele description [Variation Report for NM_003060.4(SLC22A5):c.791C>G (p.Thr264Arg)]

NM_003060.4(SLC22A5):c.791C>G (p.Thr264Arg)

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.791C>G (p.Thr264Arg)
Other names:
p.Thr264Arg
HGVS:
  • NC_000005.10:g.132385466C>G
  • NG_008982.2:g.20763C>G
  • NM_001308122.2:c.863C>G
  • NM_003060.4:c.791C>GMANE SELECT
  • NP_001295051.1:p.Thr288Arg
  • NP_003051.1:p.Thr264Arg
  • NC_000005.9:g.131721158C>G
  • NM_003060.3:c.791C>G
Protein change:
T264R
Links:
dbSNP: rs201262157
NCBI 1000 Genomes Browser:
rs201262157
Molecular consequence:
  • NM_001308122.2:c.863C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003060.4:c.791C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Renal carnitine transport defect (CDSP)
Synonyms:
CARNITINE DEFICIENCY, SYSTEMIC, DUE TO DEFECT IN RENAL REABSORPTION OF CARNITINE; CARNITINE TRANSPORTER, PLASMA-MEMBRANE, DEFICIENCY OF; CARNITINE UPTAKE DEFECT; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008919; MedGen: C0342788; Orphanet: 158; OMIM: 212140

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000632571Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 6, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002055758Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jul 15, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002576616Giacomini Lab, University of California, San Francisco
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Oct 3, 2022)
germline, not applicableresearch, in vitro

PubMed (1)
[See all records that cite this PMID]

SCV002766214Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Nov 7, 2022)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004201247Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Nov 29, 2023)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005669212Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Mar 31, 2024)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providednot applicablenot applicablenot providednot providednot providednot providednot providedin vitro
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research

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

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
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000632571.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 264 of the SLC22A5 protein (p.Thr264Arg). This variant is present in population databases (rs201262157, gnomAD 0.008%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20574985, 35281663). ClinVar contains an entry for this variant (Variation ID: 460416). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV002055758.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Giacomini Lab, University of California, San Francisco, SCV002576616.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
2not providednot providednot providednot providedin vitro PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided
2not applicablenot applicablenot providednot providedassert pathogenicitynot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766214.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: SLC22A5 c.791C>G (p.Thr264Arg) results in a non-conservative amino acid change located in the major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251456 control chromosomes (gnomAD). c.791C>G has been reported in the literature as a biallelic genotype in at least two individuals affected with Systemic Primary Carnitine Deficiency, identified through newborn screening programs (e.g. Li_2010, Martin-Rivada_2022). 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 (e.g. Frigeni_2017). Carnitine transport activity was reduced to < 3% of normal in cells expressing the variant, suggesting it negatively impacts protein function. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Three classified the variant as likely pathogenic and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004201247.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics, Fulgent Genetics, SCV005669212.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 1, 2025