rs144547521

Positions:

chr5-132390830-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_003060.4(SLC22A5):c.1193C>T(p.Pro398Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.67

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:

SLC22A5 (HGNC:):

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 11) in uniprot entity OCTN2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003060.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

PP5

Variant 5-132390830-C-T is Pathogenic according to our data. Variant chr5-132390830-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132390830-C-T is described in Lovd as [Pathogenic]. Variant chr5-132390830-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A5	NM_003060.4 linkuse as main transcript	c.1193C>T	p.Pro398Leu	missense_variant	7/10	ENST00000245407.8	NP_003051.1	O76082-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 linkuse as main transcript	c.1193C>T	p.Pro398Leu	missense_variant	7/10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251468

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

211

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000178

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2021	The SLC22A5 c.1193C>T; p.Pro398Leu variant (rs144547521) is reported in the literature in multiple individuals affected with primary carnitine deficiency (PCD), several of whom also carried an additional pathogenic variant (Amat di San Filippo 2006, Li 2010). The p.Pro398Leu variant is reported at pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 25411) and is observed in the general population at a low overall frequency of 0.01% (21/282862 alleles) in the Genome Aggregation Database. The proline at codon 398 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.515). Still, both in vitro and in vivo functional analyses of this variant demonstrate reduced cDNA expression and significantly decreased carnitine transport activity (Amat di San Filippo 2006, Frigeni 2017). Additionally, several other missense variants in the adjacent codon (p.Arg399Gln, p.Arg399Trp) are reported in individuals affected with PCD and exhibit reduced transport activity (Frigeni 2017), suggesting functional importance of this region of the protein. Based on available information, the p.Pro398Leu variant is considered to be pathogenic. References: Amat di San Filippo C et al. Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat. 2006 Jun;27(6):513-23. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. 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. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 398 of the SLC22A5 protein (p.Pro398Leu). This variant is present in population databases (rs144547521, gnomAD 0.02%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 16652335, 20574985; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25411). 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: 16652335). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 16, 2024	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2024	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: 23430858, 16652335, 25087612, 20574985, 23757202, 16602102, 28841266, 23379544, 35568002) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 25, 2023	PP4, PM2, PM3_strong, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.081

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.16

T;T

Polyphen

0.96

D;.

Vest4

0.68

MVP

0.93

MPC

0.65

ClinPred

0.68

GERP RS

6.2

Varity_R

0.71

gMVP

0.77

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