rs386134210

chr5-132387045-G-Achr5-132387045-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003060.4(SLC22A5):c.845G>A(p.Arg282Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,972 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.72

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 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132387044-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 967907.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 5-132387045-G-A is Pathogenic according to our data. Variant chr5-132387045-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 25401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132387045-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.845G>A	p.Arg282Gln	missense_variant	5/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.845G>A	p.Arg282Gln	missense_variant	5/10	1	NM_003060.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 282 of the SLC22A5 protein (p.Arg282Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 16652335, 20574985, 21922592). ClinVar contains an entry for this variant (Variation ID: 25401). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC22A5 protein function. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 16652335). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 22, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 04, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	Published functional studies found this variant is associated with significantly impaired carnitine transport (Amat di San Filippo C et al., 2006; Frigeni M et al. 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16652335, 28841266, 32371215, 33757571, 21922592, 23430858, 16602102, 26828774, 23379544, 20574985, 23520115, 20074989, 33181153, 35095998) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2023

The c.845G>A (p.R282Q) alteration is located in exon 5 (coding exon 5) of the SLC22A5 gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.845G>A alteration has been reported in homozygous and compound heterozygous state in multiple symptomatic and asymptomatic individuals diagnosed with primary carnitine deficiency (Amat di San Filippo, 2006; Li, 2010; Lee, 2010; Rose, 2012; Li, 2021; Ambrose, 2022; Martín-Rivada, 2022). This alteration has been identified as co-occurring with the pathogenic alteration SLC22A5 NM_003060 p.R254* c.760C>T in one individual, however, phase (cis or trans) was not confirmed (Li, 2021). This amino acid position is highly conserved in available vertebrate species. The p.R282Q alteration significantly reduces carnitine transport (Rose, 2012). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.2	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.045	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.88
MutPred		0.98		Gain of glycosylation at P278 (P = 0.1555);.;.;
MVP		0.98
MPC		0.84
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.68
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386134210; hg19: chr5-131722737;