rs28383481

Variant names:

• chr5-132393688-G-A
• rs28383481
• NM_003060.4:c.1463G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5 BP4_Strong BS1_Supporting BS2

The NM_003060.4(SLC22A5):​c.1463G>A​(p.Arg488His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,614,104 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R488C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (26 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:10 B:4
• Conservation: PhyloP100: 2.76

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 Benign. Variant got -7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132393687-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.017382115).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00342 (520/152254) while in subpopulation AMR AF= 0.00713 (109/15298). AF 95% confidence interval is 0.00604. There are 1 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.1463G>A	p.Arg488His	missense_variant	Exon 9 of 10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.1463G>A	p.Arg488His	missense_variant	Exon 9 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00325 AC: 817 AN: 251442 Hom.: 6 AF XY: 0.00321 AC XY: 436 AN XY: 135894

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00466

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00467 AC: 6834 AN: 1461850 Hom.: 26 Cov.: 32 AF XY: 0.00459 AC XY: 3339 AN XY: 727228

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00449

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.000917

Gnomad4 NFE exome AF: 0.00557

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.00342 AC: 520 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00343 AC XY: 255 AN XY: 74424

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00454 Hom.: 1

Bravo AF: 0.00343

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00326 AC: 396

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:10 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Renal carnitine transport defect Pathogenic:3 Uncertain:9 Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 21, 2017

Centogene AG - the Rare Disease Company

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 20, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

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: criteria provided, single submitter

Collection Method: in vitro;research

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2013

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 18, 2021

Pars Genome Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC22A5: PM5, BS2 -

Jul 30, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A142S and R488H variants in the SLC22A5 gene have been reported previously in association with systemic primary carnitine deficiency (CDSP) in patients who harbored A142S and R488H on the same SLC22A5 allele (in cis) with a third variant on the opposite allele (Amat di San Filippo et al., 2006, SLC22A5 Mutation database, www.arup.utah.edu; Mazzini et al. 2011). While the A142S variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, the R488H variant was observed with a frequency of 0.5%, 45/8600 alleles, in individuals of European American ancestry. When A142S and R488H were expressed individually in CHO cells, neither variant reduced carnitine transport (Amat di San Filippo et al., 2006). However, when A142S and R488H were present on the same allele, expression in CHO cells showed significantly impaired carnitine transport, indicating that A142S and R488H need to be present on the same SLC22A5 allele in order to impair function (Amat di San Filippo et al., 2006). Therefore when the R488H missense change is present without a second variant on the same SLC22A5 allele, it is not expected to be a pathogenic variant. -

not specified Uncertain:1 Benign:1

Aug 15, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC22A5 c.1463G>A (p.Arg488His) results in a non-conservative amino acid change located in the Major facilitator superfamily domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 1614104 control chromosomes, predominantly at a frequency of 0.0055 within the Latino subpopulation in the gnomAD database, including 21 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency phenotype (0.0046). c.1463G>A has been reported to be in cis with c.424G>T (pathogenic) in the literature in at least one individual affected with Systemic Primary Carnitine Deficiency (e.g. Amat di San Filippo_2006). The variant has been reported in at least one patient with Hypoketotic hypoglycemia and Abnormality of carnitine metabolism, in trans with a VUS (Barbosa-Gouveia_2021). In addition, c.1463G>A in isolation has been reported in general population and is not in linkage disequilibrium with c.424G>T (gnomAD database, Toh_2010). Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of wild type Carnitine transport activity (Amat di San Filippo_2006, Frigeni_2017). The following publications have been ascertained in the context of this evaluation (PMID: 34440436, 21126579, 28841266, 20208395). ClinVar contains an entry for this variant (Variation ID: 38794). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 17, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Arg488His var iant in SLC22A5 has been reported in the compound heterozgous state in at least 5 individuals with primary carnitine deficiency (di San Filippo 2006, Mazzini 20 11, Rose 2012, Frigeni 2017, Thompson 2018); however in all of these individuals a second variant (p.Ala142Ser) was identified on the same copy of the SLC22A5 g ene (in cis). Functional studies indicate that p.Arg488His does not significantl y impact carnitine transport alone, and must occur in cis with p.Ala142Ser to im pact protein function (di San Filippo 2006). However, these types of assays may not accurately represent biological function. The p.Arg488His variant has been i dentified in 0.47% (598/126640) of European chromosomes and 0.32% (884/277154) o f total chromosomes by the Genome Aggregation Database, including 6 homozygotes (gnomAD, http://gnomad.broadinstitute.org). It is also present in ClinVar with c onfliciting interpretations of pathogenicity (Variation ID# 38794). Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact the protein. Finally, another variant at the same position ( p.Arg488Cys) has been identified in the homozygous state in one individual with primary carnitine deficiency (Schimmenti 2007). In summary, while the clinical s ignificance of this variant is uncertain, these data suggest that, in the absenc e of p.Ala142Ser, the p.Arg488His variant is unlikely to be disease causing. AMC G/AMP criteria applied: PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.084	T;T
Polyphen		0.97	D;.
Vest4		0.73
MVP		0.80
MPC		0.79
ClinPred		0.038	T
GERP RS		5.8
Varity_R		0.30
gMVP		0.53

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: rs28383481; hg19: chr5-131729380;