rs72552732

Positions:

• chr5-132392484-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. T440T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain 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	UniProt
SLC22A5	NM_003060.4	c.1319C>T	p.Thr440Met	missense_variant	8/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.1319C>T	p.Thr440Met	missense_variant	8/10	1	NM_003060.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152200 Hom.: 0 Cov.: 32

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: 3 AN: 251494 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

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: 13 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727242

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: 6 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74348

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.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2019	- -
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	Invitae	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, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 02, 2020	- -
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	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	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 22, 2023	PM1, PM2, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

not provided Pathogenic:2

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2013	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
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	D
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

Other links and lift over

dbSNP: rs72552732; hg19: chr5-131728176;