VCV000006420.24 - ClinVar

NM_003060.4(SLC22A5):c.632A>G (p.Tyr211Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003060.4(SLC22A5):c.632A>G (p.Tyr211Cys)

Variation ID: 6420 Accession: VCV000006420.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.1 5: 132384281 (GRCh38) [ NCBI UCSC ] 5: 131719973 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 23, 2014	Jun 17, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003060.4:c.632A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003051.1:p.Tyr211Cys	missense
NM_001308122.2:c.704A>G	NP_001295051.1:p.Tyr235Cys	missense
NC_000005.10:g.132384281A>G
NC_000005.9:g.131719973A>G
NG_008982.2:g.19578A>G
	O76082:p.Tyr211Cys

... more HGVS ... less HGVS

Protein change

Y211C, Y235C

Other names

p.Y211C:TAT>TGT

Canonical SPDI

NC_000005.10:132384280:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

UniProtKB: O76082#VAR_009253 OMIM: 603377.0012 dbSNP: rs121908888 ClinGen: CA312941 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SLC22A5		-	-	GRCh38 GRCh37	1174	1217

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Renal carnitine transport defect	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV000006789.32
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 19, 2023	RCV000186136.15
Decreased circulating carnitine concentration	Pathogenic (1)	no assertion criteria provided	Dec 2, 2020	RCV002226443.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 01, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000339309.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC22A5 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Likely pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal carnitine transport defect Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002055807.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Likely pathogenic (Oct 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002783394.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Sep 19, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000239161.11 First in ClinVar: Jul 18, 2015 Last updated: Sep 30, 2023	Comment: Published functional studies found cells expressing the variant showed no carnitine transport activity compared to wild-type (Frigeni et al., 2017); In silico analysis supports that … (more) Published functional studies found cells expressing the variant showed no carnitine transport activity compared to wild-type (Frigeni et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26828774, 25087612, 23379544, 10480371, 28841266, 32778825) (less)
Pathogenic (Nov 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001232818.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 10480371‚ 28841266 Comment: This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 211 of the SLC22A5 protein … (more) This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 211 of the SLC22A5 protein (p.Tyr211Cys). This variant is present in population databases (rs121908888, gnomAD 0.003%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 10480371). ClinVar contains an entry for this variant (Variation ID: 6420). 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: 28841266). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004201257.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jul 01, 1999)	no assertion criteria provided Method: literature only	CARNITINE DEFICIENCY, SYSTEMIC PRIMARY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026985.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 29, 2018	Publications: PubMed (3) PubMed: 10480371‚ 3215194‚ 2199596 Comment on evidence: In 2 unrelated patients with classic systemic carnitine deficiency (CDSP; 212140), Vaz et al. (1999) found homozygosity for the same missense mutation, 632A-G, which changes … (more) In 2 unrelated patients with classic systemic carnitine deficiency (CDSP; 212140), Vaz et al. (1999) found homozygosity for the same missense mutation, 632A-G, which changes the tyrosine at amino acid position 211 into a cysteine (Y211C). The first patient had been reported by Rodrigues Pereira et al. (1988) and by Scholte et al. (1990). The second patient was admitted to hospital at 7 months of age because of failure to thrive. Physical examination showed dilated cardiomyopathy. Cardiac decompensation had existed from the age of 5 months. Treatment with digoxin and diuretics was started. At the age of 20 months, she presented with lowered consciousness, respiratory insufficiency, hypoglycemia, hyperammonemia, elevated transaminases, and low plasma carnitine concentrations. With carnitine therapy, improvement of the echocardiographic findings was noted by the age of 2 years. At the age of 5.5 years, the echocardiograph was almost normal. (less)
Pathogenic (Dec 02, 2020)	no assertion criteria provided Method: clinical testing	Carnitine deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002078309.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
Pathogenic (Dec 02, 2020)	no assertion criteria provided Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002107432.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022
Likely pathogenic (Dec 29, 2015)	no assertion criteria provided Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000485512.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 23, 2019	Publications: PubMed (1) PubMed: 10480371

Comment:

Published functional studies found cells expressing the variant showed no carnitine transport activity compared to wild-type (Frigeni et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26828774, 25087612, 23379544, 10480371, 28841266, 32778825)

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 211 of the SLC22A5 protein (p.Tyr211Cys). This variant is present in population databases (rs121908888, gnomAD 0.003%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 10480371). ClinVar contains an entry for this variant (Variation ID: 6420). 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: 28841266). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Functional and molecular studies in primary carnitine deficiency.	Frigeni M	Human mutation	2017	PMID: 28841266
Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency.	Vaz FM	Human genetics	1999	PMID: 10480371
Primary carnitine deficiency.	Scholte HR	Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie	1990	PMID: 2199596
Cardiomyopathy associated with carnitine loss in kidneys and small intestine.	Rodrigues Pereira R	European journal of pediatrics	1988	PMID: 3215194
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC22A5	-	-	-	-

Text-mined citations for rs121908888 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_003060.4(SLC22A5):c.632A>G (p.Tyr211Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908888 ...