NM_003060.4(SLC22A5):c.1400C>G (p.Ser467Cys) AND Renal carnitine transport defect

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Mar 28, 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:: RCV000022379.40

Allele description [Variation Report for NM_003060.4(SLC22A5):c.1400C>G (p.Ser467Cys)]

NM_003060.4(SLC22A5):c.1400C>G (p.Ser467Cys)

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.1400C>G (p.Ser467Cys)

HGVS:

NC_000005.10:g.132392565C>G
NG_008982.2:g.27862C>G
NM_001308122.2:c.1472C>G
NM_003060.4:c.1400C>GMANE SELECT
NP_001295051.1:p.Ser491Cys
NP_001295051.1:p.Ser491Cys
NP_003051.1:p.Ser467Cys
NP_003051.1:p.Ser467Cys
NC_000005.9:g.131728257C>G
NM_001308122.1:c.1472C>G
NM_003060.3:c.1400C>G
O76082:p.Ser467Cys
p.Ser491Cys

Protein change:

S491C

Links:

UniProtKB: O76082#VAR_022566; dbSNP: rs60376624

NCBI 1000 Genomes Browser:

rs60376624

Molecular consequence:

NM_001308122.2:c.1472C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003060.4:c.1400C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000632528	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20074989, 20574985, 21922592, 23090741, 10545605, 12183691, 28492532
SCV001162982	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 28, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193898	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Likely pathogenic (Jan 3, 2020)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30904546, 28841266, 20074989, 23090741, 10545605, 12183691 Citation Link,
SCV001462823	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002022599	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002055829	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002074341	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 19, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10545605, 32371215 Citation Link,
SCV002790443	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 17, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004800872	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing
SCV004812654	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10545605, 20574985, 21922592, 25846890, 28841266, 37628339, 25741868

Help

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Han	germline	yes	2	not provided	not provided	2	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

Expanded newborn screening for inherited metabolic disorders and genetic characteristics in a southern Chinese population.

Lin Y, Zheng Q, Zheng T, Zheng Z, Lin W, Fu Q.

Clin Chim Acta. 2019 Jul;494:106-111. doi: 10.1016/j.cca.2019.03.1622. Epub 2019 Mar 21.

PubMed [citation]

PMID:: 30904546

See all PubMed Citations (13)

PMC

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Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000632528.9

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

Description

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 467 of the SLC22A5 protein (p.Ser467Cys). This variant is present in population databases (rs60376624, gnomAD 0.2%). This missense change has been observed in individuals with SLC22A5-related conditions (PMID: 10545605, 20074989, 20574985, 21922592, 23090741). ClinVar contains an entry for this variant (Variation ID: 25423). 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%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 10545605, 12183691). 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 Baylor Genetics, SCV001162982.2

#	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

From Myriad Genetics, Inc., SCV001193898.2

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

Description

NM_003060.3(SLC22A5):c.1400C>G(S467C) is classified as likely pathogenic in the context of primary carnitine deficiency. Sources cited for classification include the following: PMID: 30904546, 28841266, 20074989, 23090741, 10545605 and 12183691. Classification of NM_003060.3(SLC22A5):c.1400C>G(S467C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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 Natera, Inc., SCV001462823.1

#	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 Revvity Omics, Revvity, SCV002022599.3

#	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, SCV002055829.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074341.1

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

Description

Variant summary: SLC22A5 c.1400C>G (p.Ser467Cys) results in a non-conservative amino acid change located in the major facilitator superfamily domain 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 0.00017 in 251468 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00017 vs 0.0046), allowing no conclusion about variant significance. c.1400C>G is a common pathogenic mutation found in individuals with primary carnitine deficiency or carnitine uptake defect (ie. Koizumi_1999, Lin_2020). In vitro functional analysis revealed the variant to reduce L-carnitine uptake to 11% of the normal control (Koizumi_2020). Eight 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/likely 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 Fulgent Genetics, Fulgent Genetics, SCV002790443.1

#	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 Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital, SCV004800872.1

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

Description

PS3+PM3_S+PP1_S+PP3+PP4

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

From Molecular Genetics, Royal Melbourne Hospital, SCV004812654.1

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

Description

This sequence change in SLC22A5 is predicted to replace serine with serine at codon cysteine, p.(Ser467Cys). The serine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the transmembrane major facilitator superfamily (MFS) profile domain. There is a large physicochemical difference between serine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.2% (98/44,876 alleles) in the East Asian population. This variant has been detected in the homozygous and compound heterozygous state in multiple individuals with a diagnosis of systemic carnitine deficiency (SCD) mainly ascertained through newborn screening and asymptomatic (PMID: 20574985, 25846890, 21922592, 28841266, 37628339). The variant segregates with SCD in at least one family (PMID: 25846890). In vitro functional assays with limited validation in mammalian cell lines demonstrate the variant significantly reduces carnitine uptake (PMID: 10545605, 28841266). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.756). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1, PP3, PS3_Supporting.

#	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

Last Updated: Nov 30, 2024

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