rs11568520

chr5-132370023-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_003060.4(SLC22A5):c.51C>G(p.Phe17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,420 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.755

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]

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

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132370023-C-G is Pathogenic according to our data. Variant chr5-132370023-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 25350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3337777).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.51C>G	p.Phe17Leu	missense_variant	1/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.51C>G	p.Phe17Leu	missense_variant	1/10	1	NM_003060.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000124 AC: 31 AN: 249224 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00164

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461074 Hom.: 1 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74500

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000793

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 17 of the SLC22A5 protein (p.Phe17Leu). This variant is present in population databases (rs11568520, gnomAD 0.2%). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 20074989, 20574985, 23520115). ClinVar contains an entry for this variant (Variation ID: 25350). 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: 16931768). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 29, 2023	- -
Pathogenic, criteria provided, single submitter	in vitro;research	Giacomini Lab, University of California, San Francisco	Oct 03, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	-	PS3+PM3_VS+PP1_S+PP3+PP4 -
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	Mar 16, 2023	Variant summary: SLC22A5 c.51C>G (p.Phe17Leu) results in a non-conservative amino acid change in 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 0.00012 in 249224 control chromosomes (gnomAD), predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.0016 vs 0.0046), allowing no conclusion about variant significance. c.51C>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Lin_2021, Liammongkolkul_2023). These data indicate that the variant is very likely to be associated with disease. The variant was found to result in decreased L-carntine transport, with the most pronounced variant effect resulting in <20% normal activity which may be the result of incorrect localization to the cytoplasm instead of the plasma membrane (e.g. Urban_2006, Frigeni_2017). Eight ClinVar submitters have assessed the variant since 2014: all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 02, 2020	NM_003060.3(SLC22A5):c.51C>G(F17L) is classified as pathogenic in the context of primary carnitine deficiency. Sources cited for classification include the following: PMID 18337137, 30904546, 30838026, 29132460, 28841266, 25132046, 23520115, 23798014, 20574985 and 16931768. Classification of NM_003060.3(SLC22A5):c.51C>G(F17L) 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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2022	Functional analysis of p.(F17L) found that it is associated with decreased function, impaired carnitine transport, and distinct subcellular localization (Urban et al., 2006); 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: 25132046, 20074989, 28711408, 23520115, 20574985, 28186590, 19940846, 26828774, 28841266, 29132460, 30904546, 31364285, 31472821, 31980526, 33050909, 33757571, 33560599, 32778825, 33181153, 16931768) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2018	The SLC22A5 c.51C>G; p.Phe17Leu variant (rs11568520) has been described as a common pathogenic variant in the Chinese population (Chen 2013) and has been identified in the homozygous and compound heterozygous states in patients affected with and newborns screening positive for primary carnitine deficiency (Chen 2013, Han 2014, Lee 2010, Li 2010). It is reported as pathogenic in ClinVar (Variation ID: 25350) and is observed in the general population at a low overall frequency of 0.01% (29/275524 alleles) in the Genome Aggregation Database. The phenylalanine at codon 17 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant to be deleterious to protein function. Additionally, functional analysis of the variant protein demonstrates defective trafficking to the plasma membrane and reduced enzymatic function (Urban 2006). Based on available information, this variant is considered pathogenic. References: Chen Y et al. Carnitine uptake defect (primary carnitine deficiency): risk in genotype-phenotype correlation. Hum Mutat. 2013;34(4):655. 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 F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010;31(8):E1632-51. Urban T et al. Functional genetic diversity in the high-affinity carnitine transporter OCTN2 (SLC22A5). Mol Pharmacol. 2006;70(5):1602-11. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;.
Vest4		0.32
MutPred		0.93		Loss of methylation at R19 (P = 0.3265);Loss of methylation at R19 (P = 0.3265);
MVP		0.96
MPC		0.65
ClinPred		0.85	D
GERP RS		3.2
Varity_R		0.82
gMVP		0.90

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: rs11568520; hg19: chr5-131705715;