rs72552732

Positions:

chr5-132392484-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_003060.4(SLC22A5):c.1319C>T(p.Thr440Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.54

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 16 ACMG points.

PM1

In a transmembrane_region Helical; Name=10 (size 20) in uniprot entity OCTN2_HUMAN there are 9 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, 0.987

PP5

Variant 5-132392484-C-T is Pathogenic according to our data. Variant chr5-132392484-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 25416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392484-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A5	NM_003060.4 linkuse as main transcript	c.1319C>T	p.Thr440Met	missense_variant	8/10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 linkuse as main transcript	c.1319C>T	p.Thr440Met	missense_variant	8/10	1	NM_003060.4	ENSP00000245407	P1	O76082-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251494

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000647

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 20, 2021	Variant summary: SLC22A5 c.1319C>T (p.Thr440Met) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) 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 1.2e-05 in 251494 control chromosomes. c.1319C>T has been widely reported in the literature in multiple individuals affected with Systemic Primary Carnitine Deficiency and has been subsequently cited by others (example, Lamhonwah_2002, Wattanasirichaigoon_2006, Amat_2006, Rose_2012, Li_2010, Angelini_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Lamhonwah_2002). The most pronounced variant effect results in <10% of normal carnitine uptake in skin fibroblasts from a homozygous affected individual. Six 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 18, 2018	The SLC22A5 c.1319C>T; p.Thr440Met variant (rs72552732), is reported in the literature in a homozygous or compound heterozygous state in multiple individuals affected with primary carnitine deficiency (Angelini 2015, Frigeni 2017, Lamhonwah 2002, Li 2010, Thompson 2018, Wattanasirichaigoon 2006) and cardiomyopathy (Papadopoulou-Legbelou 2017). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 25416), and is found in the non-Finnish European population with an overall allele frequency of 0.0027% (3/111718 alleles) in the Genome Aggregation Database. Functional analyses of the variant protein shows impaired carntitine transport (Amat di San Filippo 2006). The threonine at codon 440 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this 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. Angelini C et al. Spectrum of metabolic myopathies. Biochim Biophys Acta. 2015 Apr;1852(4):615-21. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Lamhonwah AM et al. Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy. Am J Med Genet. 2002 Aug 15;111(3):271-84. 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. Papadopoulou-Legbelou K et al. Dilated Cardiomyopathy as the Only Clinical Manifestation of Carnitine Transporter Deficiency. Indian J Pediatr. 2017 Mar;84(3):231-233. Thompson ML et al. Genomic sequencing identifies secondary findings in a cohort of parent study participants. Genet Med. 2018 Apr 12. doi: 10.1038/gim.2018.53. (Epub ahead of print) Wattanasirichaigoon D et al. Pericardial effusion in primary systemic carnitine deficiency. J Inherit Metab Dis. 2006 Aug;29(4):589. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	Across a selection of the literature, the SLC22A5 c.1319C>T (p.Thr440Met) missense variant has been reported in ten individuals with systemic primary carnitine deficiency, including in one in a homozygous state, in eight in a compound heterozygous state, and in one in a heterozygous state (Lamhonwah et al. 2002; Amat di San Filippo et al. 2006; Li et al. 2010). The variant is also found in three unaffected heterozygotes. The p.Thr440Met variant is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium based on two alleles in an area of good coverage, so the variant is presumed to be rare. Functional studies performed on cultured patient skin fibroblasts and in CHO cells were performed to evaluate carnitine uptake and transport levels compared to wildtype. The p.Thr440Met variant was found to have carnitine transport level that was less than 10% of wildtype (Amat di San Filippo et al. 2006). Lamhonwah et al. (2002) reported that the carnitine uptake values ranged from 2.8% in a patient homozygous for the variant to 20% in a compound heterozygote, in comparison to controls. Based on the collective evidence, the p.Thr440Met variant is classified as pathogenic for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 440 of the SLC22A5 protein (p.Thr440Met). This variant is present in population databases (rs72552732, gnomAD 0.003%). This missense change has been observed in individuals with primary carnitine deficiency (PMID: 12210323, 16652335, 16830263, 20574985, 21922592, 24997454). This variant is also known as c.1540C>T. ClinVar contains an entry for this variant (Variation ID: 25416). 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: 12210323, 21922592). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 21, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 22, 2023	PM1, PM2, PP2, PP3, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2020	Published functional studies in CHO cells demonstrate a damaging effect on carnitine transport activity (Frigeni et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 27807682, 29790872, 16865412, 12210323, 16830263, 20574985, 16652335, 24997454, 28841266, 23379544, 21922592, 16602102, 32276632) -

Decreased circulating carnitine concentration

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 02, 2020

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2016

- -

SLC22A5-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The SLC22A5 c.1319C>T variant is predicted to result in the amino acid substitution p.Thr440Met. This variant has been reported, in the homozygous or compound heterozygous state, in multiple patients with systemic primary carnitine deficiency (e.g., Lamhonwah et al. 2002. PubMed ID: 12210323; Amat di San Filippo et al. 2006. PubMed ID: 16652335; Li et al. 2010. PubMed ID: 20574985; Angelini. 2015. PubMed ID: 24997454). In in vitro assays, the p.Thr440Met substitution has been shown to nearly abolish carnitine transport (Amat di San Filippo et al. 2006. PubMed ID: 16652335; Frigeni et al. 2017. PubMed ID: 28841266). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on the available evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

D;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.8

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.92

MutPred

0.90

Gain of stability (P = 0.0076);.;

MVP

0.99

MPC

0.82

ClinPred

1.0

GERP RS

6.2

Varity_R

0.81

gMVP

0.86

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