rs386134223

chr5-132392577-G-Achr5-132392577-G-Cchr5-132392577-G-T

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.1412G>A(p.Arg471His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,868 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R471C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.57

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr5-132392576-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 460398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 5-132392577-G-A is Pathogenic according to our data. Variant chr5-132392577-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.1412G>A	p.Arg471His	missense_variant	8/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.1412G>A	p.Arg471His	missense_variant	8/10	1	NM_003060.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 471 of the SLC22A5 protein (p.Arg471His). 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: 14605509, 25132046). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 25426). 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: 16652335). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 10, 2020	The SLC22A5 c.1412G>A (p.Arg471His) variant, alternately known as c.1484G>A (p.Arg495His) when annotated on the NM_001308122.1 transcript, is a missense variant that has been reported in at least four individuals from two unrelated families with systemic primary carnitine deficiency (SPCD). Spiekerkoetter et al. (2003) describe a consanguineous Turkish family in which a father and two sons are homozygous for the p.Arg471His variant. All individuals displayed low serum carnitine and deficient carnitine uptake in fibroblasts, however only one son was symptomatic. Han et al. (2014) report a Chinese child with vomiting, Reye-like syndrome, fever, pneumonia, hypoglycemia, hyperammonemia, elevated creatine kinase, hepatomegaly, and hydrocephalus who was found to have the p.Arg471His variant and a stop-gained variant, presumably in a compound heterozygous state. In vitro studies in which the p.Arg471His variant was expressed in Chinese hamster ovary (CHO) cells displayed carnitine transport rates of <2% of wild-type (di San Filippo et al. 2006). The p.Arg471His variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Additionally, Arg471 is a conserved residue located in transmembrane domain 11, a region involved in substrate recognition and transport, and other missense variants impacting the Arg471 residue have been reported in the literature and submitted to ClinVar with likely pathogenic or pathogenic classifications for SPCD (Longo et al. 2016; Landrum et al. 2018). Based on the collective evidence and application of the ACMG criteria, the p.Arg471His variant is classified as likely pathogenic for systemic primary carnitine deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2023	Variant summary: SLC22A5 c.1412G>A (p.Arg471His) 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 was absent in 251434 control chromosomes (gnomAD). c.1412G>A has been reported in the literature as a biallelic genotype in symptomatic and asymptomatic individuals affected with Systemic Primary Carnitine Deficiency (e.g. Spiekerkoetter_2003, Han_2014, Liammongkolkul_2023). These data indicate that the variant is very likely to be associated with disease. Furthermore, publications reporting experimental evidence evaluating an impact on protein function in CHO cells found that the variant results in <2% transport activity compared to the WT protein (e.g. Amat di San Filippo_2006, Frigeni_ 2017). The following publications have been ascertained in the context of this evaluation (PMID: 16652335, 28841266, 25132046, 36321377, 14605509). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=2)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.93		Loss of methylation at R471 (P = 0.0129);.;
MVP		0.98
MPC		0.90
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.82
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs386134223; hg19: chr5-131728269; COSMIC: COSV99809649; COSMIC: COSV99809649;