5-132370220-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP4

The NM_003060.4(SLC22A5):c.248G>T(p.Arg83Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,586,198 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 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13U:1

Conservation

PhyloP100: 5.29

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:

MIR3936HG (HGNC:40538): (MIR3936 host gene)

MIR3936HG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 5-132370220-G-T is Pathogenic according to our data. Variant chr5-132370220-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132370220-G-T is described in Lovd as [Pathogenic]. Variant chr5-132370220-G-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.3242846). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4 link	c.248G>T	p.Arg83Leu	missense_variant	Exon 1 of 10	ENST00000245407.8	NP_003051.1	O76082-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 link	c.248G>T	p.Arg83Leu	missense_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152232

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:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000268

AC:

AN:

193890

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

106592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00187

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

153

AN:

1433848

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

101

AN XY:

710968

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00178

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000675

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000287

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:10Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.248G>Tp.Arg83Leu in the SLC22A5 gene has been reported previously in homozygous/ heterozygous/ compound heterozygous state in multiple individuals with Primary carnitine deficiency. Experimental studies have shown that this missense change affects SLC22A5 function El-Hattab et al., 2010; Filippo CA, et al., 2011. The variant has 0.03% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance/Likely Pathogenic/ Pathogenic multiple submissions. The amino acid Arginine at position 83 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Arg83Leu in SLC22A5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -

Feb 02, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SLC22A5 c.248G>T (p.Arg83Leu) variant is located in an extracellular loop close to putative glycosylation sites of SLC22A5 (via Filippo_2011) involves the alteration of a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 22/50892 (1/2313), predominantly in the South Asian cohort, 20/11664 (1/583), which does not exceed the estimated maximal expected allele frequency for a pathogenic SLC22A5 variant of 1/219. Multiple publications have cited the variant in affected homozygous and compound heterozygous individuals, and the variant has also been reported in asymptomatic individuals with serum carnitine deficiency. In addition, a functional study (Filippo_2011) indicates the variant impaired glycosylation and maturation of SLC22A5 to the plasma membrane. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC22A5 c.248G>T; p.Arg83Leu variant (rs72552726) is reported in the literature in numerous individuals affected with primary carnitine deficiency (PCD), both in the homozygous state and in individuals with a second pathogenic SLC22A5 variant (El-Hattab 2010, Han 2014, Li 2010, Makhseed 2004, Rose 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 25361) and has been observed to co-segregate with disease in affected families (El-Hattab 2010, Makhseed 2004). The p.Arg83Leu variant is found in the South Asian population with an overall allele frequency of 0.19% (51/27338 alleles) in the Genome Aggregation Database, though the prevalence of PCD in the general population may be confounded by asymptomatic individuals (Magoulas 2012). The arginine at codon 83 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses indicate that the p.Arg83Leu variant has negligible carnitine transport activity (Amat di San Filippo 2006, Amat di San Filippo 2011, Frigeni 2017, Makhseed 2004, Rose 2012), and it is poorly expressed and aberrantly localized to the cytoplasm, possibly due to loss of glycosylation (Amat di San Filippo 2011). Based on available information, this variant is considered to be pathogenic. References: Amat di San Filippo C et al. Glycosylation of the OCTN2 carnitine transporter: study of natural mutations identified in patients with primary carnitine deficiency. Biochim Biophys Acta. 2011 Mar;1812(3):312-20. Amat di San Filippo C et al. Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat. 2006 Jun;27(6):513-23. El-Hattab A et al. Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects. Genet Med. 2010; 12(1):19-24. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Han L et al. Analysis of genetic mutations in Chinese patients with systemic primary carnitine deficiency. Eur J Med Genet. 2014 Oct;57(10):571-5. Li FY 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. Magoulas P et al. Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012; 7:68. Makhseed N et al. Carnitine transporter defect due to a novel mutation in the SLC22A5 gene presenting with peripheral neuropathy. J Inherit Metab Dis. 2004;27(6):778-80. Rose E et al. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012; 33(1):118-23. -

Jan 06, 2020

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_003060.3(SLC22A5):c.248G>T(R83L) is classified as likely pathogenic in the context of primary carnitine deficiency. Sources cited for classification include the following: PMID 24516753, 25132046, 20574985, 16652335, 21126579, 21922592 and 15617188. Classification of NM_003060.3(SLC22A5):c.248G>T(R83L) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening. -

Oct 11, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2022

Giacomini Lab, University of California, San Francisco

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: in vitro;research

- -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 83 of the SLC22A5 protein (p.Arg83Leu). This variant is present in population databases (rs72552726, gnomAD 0.2%). This missense change has been observed in individuals with primary carnitine deficiency (PMID: 15617188, 20574985, 21126579, 21922592; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 25361). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 15617188, 16652335, 21126579). For these reasons, this variant has been classified as Pathogenic. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Sep 14, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in association with primary/systemic carnitine deficiency (PCD) in patients who were homozygous for the R83L variant, as well as in both an infant who was identified who had low free carnitine levels by newborn screening and in the infant's affected mother (Makhseed et al., 2004; Li et al., 2010; El-Hattab et al., 2010); Reported with a second pathogenic variant in the asymptomatic mother of an infant identified with low free carnitine levels by newborn screening (Rose et al., 2012); In functional studies R83L impaired maturation of the transporter to the plasma membrane (Filippo et al., 2011), and reduced carnitine transport to less than 1% in CHO cell expression studies (Frigeni et al., 2017); 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: 15714519, 23430858, 28841266, 20027113, 26589311, 16652335, 21126579, 16602102, 15617188, 26828774, 20574985, 21922592, 25132046) -

Carnitine deficiency

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3,PP1,PM3 (strong),PM2,PM5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

0.049

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.84

Loss of MoRF binding (P = 0.0314);Loss of MoRF binding (P = 0.0314);

MVP

0.96

MPC

0.68

ClinPred

0.66

GERP RS

5.5

Varity_R

0.89

gMVP

0.93

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