rs60376624

Positions:

chr5-132392565-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4

The NM_003060.4(SLC22A5):c.1400C>G(p.Ser467Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000694 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 5.71

Variant links:

Genes affected

SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a transmembrane_region Helical; Name=11 (size 20) in uniprot entity OCTN2_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_003060.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-132392565-C-G is Pathogenic according to our data. Variant chr5-132392565-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392565-C-G is described in Lovd as [Pathogenic]. Variant chr5-132392565-C-G is described in Lovd as [Pathogenic]. Variant chr5-132392565-C-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.22745547). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A5	NM_003060.4 link	c.1400C>G	p.Ser467Cys	missense_variant	8/10	ENST00000245407.8	NP_003051.1	O76082-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 link	c.1400C>G	p.Ser467Cys	missense_variant	8/10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251468

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00217

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00212

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 05, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 03, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2020	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	-	PS3+PM3_S+PP1_S+PP3+PP4 -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2018	The SLC22A5 c.1400C>G; p.Ser467Cys variant (rs60376624) has been described in the homozygous and compound heterozygous states in individuals affected with primary carnitine deficiency or carnitine uptake deficiency (Koizumi 1999, Li 2010, Rose 2012, Yoon 2012). It is reported as pathogenic in ClinVar (Variation ID: 25423) and observed in the East Asian population at an overall frequency of 0.2% (43/18870 alleles) in the Genome Aggregation Database. The serine at codon 467 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. Additionally, functional analyses of the variant protein demonstrate a significant reduction in L-carnitine uptake (Koizumi 1999, Rose 2012). Based on available information, this variant is considered pathogenic. References: Koizumi A et al. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet. 1999 Nov;8(12):2247-54. Li F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010 Aug;31(8):E1632-51. Rose E et al. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012 Jan;33(1):118-23. Yoon Y et al. SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation. Ann Clin Lab Sci. 2012 Fall;42(4):424-8. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2022	In vitro expression studies in HEK cells indicate that S467C has significantly reduced L-carnitine uptake relative to a normal control (Koizumi et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28186590, 20208395, 25377941, 26589311, 25846890, 23090741, 12183691, 10545605, 26828774, 27317853, 29581464, 28841266, 20074989, 20574985, 29132460, 30885166, 30863740, 31637888, 32595695, 33757571, 33560599, 33181153) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.6

H;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.1

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.82

MVP

0.99

MPC

0.79

ClinPred

0.35

GERP RS

6.0

Varity_R

0.86

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over