NM_003060.4(SLC22A5):c.364G>T (p.Asp122Tyr) AND Renal carnitine transport defect

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 2, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000022318.18

Allele description [Variation Report for NM_003060.4(SLC22A5):c.364G>T (p.Asp122Tyr)]

NM_003060.4(SLC22A5):c.364G>T (p.Asp122Tyr)

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.364G>T (p.Asp122Tyr)
Other names:
p.D122Y:GAC>TAC
HGVS:
  • NC_000005.10:g.132370336G>T
  • NG_008982.2:g.5633G>T
  • NM_001308122.1:c.364G>T
  • NM_001308122.2:c.364G>T
  • NM_003060.4:c.364G>TMANE SELECT
  • NP_001295051.1:p.Asp122Tyr
  • NP_001295051.1:p.Asp122Tyr
  • NP_003051.1:p.Asp122Tyr
  • NC_000005.9:g.131706028G>T
  • NM_003060.3:c.364G>T
  • O76082:p.Asp122Tyr
Links:
UniProtKB: O76082#VAR_064118; dbSNP: rs201082652
NCBI 1000 Genomes Browser:
rs201082652
Molecular consequence:
  • NM_001308122.1:c.364G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001308122.2:c.364G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003060.4:c.364G>T - missense variant - [Sequence Ontology: SO:0001583]

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000632547Invitaecriteria provided, single submitter
Pathogenic
(Nov 2, 2020)
germlineclinical testing

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

SCV000886116ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Apr 10, 2020)
germlineclinical testing

Citation Link,

SCV001132488Counsylno assertion criteria providedUncertain significance
(Dec 15, 2018)
unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001162975Baylor Geneticscriteria provided, single submitter
Pathogenicgermlineclinical testing

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

SCV001423613Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospitalcriteria provided, single submitter
Likely pathogenic
(Oct 9, 2018)
germlineclinical testing

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

SCV002022598PerkinElmer Genomicsno assertion criteria providedLikely pathogenic
(Aug 26, 2021)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Functional analysis of pharmacogenetic variants of human organic cation/carnitine transporter 2 (hOCTN2) identified in Singaporean populations.

Toh DS, Murray M, Pern Tan K, Mulay V, Grewal T, Lee EJ, Zhou F.

Biochem Pharmacol. 2011 Dec 1;82(11):1692-9. doi: 10.1016/j.bcp.2011.08.008. Epub 2011 Aug 16.

PubMed [citation]
PMID:
21864509
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000632547.6

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

Description

This sequence change replaces aspartic acid with tyrosine at codon 122 of the SLC22A5 protein (p.Asp122Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs201082652, ExAC 0.07%). This variant has been reported in combination with another SLC22A5 variant in individuals affected with primary carnitine deficiency (Invitae). An individual with an abnormal newborn screening result consistent with a low free carnitine or plasma carnitine deficiency was reported to be heterozygous but no other SLC22A5 allele present (PMID: 20574985). ClinVar contains an entry for this variant (Variation ID: 25371). Experimental studies have shown that this missense change causes a markedly impaired transport function of the channel in vitro (PMID: 21864509). For these reasons, this variant has been classified as Pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000886116.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The SLC22A5 c.364G>T; p.Asp122Tyr variant (rs201082652) has been reported in an individual with myopathy, but its clinical significance was not determined (Li 2010). It has also been found heterozygously in an individual tested at ARUP Laboratories with low plasma carnitine levels and transporter activity (in fibroblast) at approximately 53 percent of wildtype (ARUP PCD database). Functional characterization in HEK293 cells indicate that the variant protein shows reduced carnitine transport activity (<10 percent of wildtype) and absence of the protein at the plasma membrane, likely due to the accumulation of the variant protein in the endoplasmic reticulum and Golgi (Toh 2011). The p.Asp122Tyr variant is reported in ClinVar (Variation ID: 25371), and found in the general population with an overall allele frequency of 0.039% (106/271794 alleles) in the Genome Aggregation Database. The aspartic acid at residue 122 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: ARUP PCD database: http://www.arup.utah.edu/database/OCTN2/OCTN2_display.php Li F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010; 31(8):E1632-51. Toh D et al. Functional analysis of pharmacogenetic variants of human organic cation/carnitine transporter 2 (hOCTN2) identified in Singaporean populations. Biochem Pharmacol. 2011; 82(11):1692-9.

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

From Counsyl, SCV001132488.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001162975.1

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

From Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital, SCV001423613.1

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

Description

[ACMG/AMP: PS3, PM2, PM3, PP3] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], is predicted to be damaging by multiple functional prediction tools [PP3].

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

From PerkinElmer Genomics, SCV002022598.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 28, 2021

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