rs267607053

Variant names:

• chr5-132392489-GC-AT
• rs267607053
• NM_003060.4:c.1324_1325delGCinsAT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PP5_Very_Strong

The NM_003060.4(SLC22A5):​c.1324_1325delGCinsAT​(p.Ala442Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1
• Conservation: PhyloP100: 5.77

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 14 ACMG points.

• PS1: Transcript NM_003060.4 (SLC22A5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a transmembrane_region Helical; Name=10 (size 20) in uniprot entity OCTN2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132392489-GC-AT is Pathogenic according to our data. Variant chr5-132392489-GC-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.1324_1325delGCinsAT	p.Ala442Ile	missense_variant		ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.1324_1325delGCinsAT	p.Ala442Ile	missense_variant		1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:7 Uncertain:1

Feb 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2019

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 442 of the SLC22A5 protein (p.Ala442Ile). This variant is present in population databases (rs267607053, gnomAD 0.001%). This missense change has been observed in individual(s) with primary carnitine deficiency and systemic carnitine deficiency (PMID: 20027113, 21922592, 28841266). ClinVar contains an entry for this variant (Variation ID: 6428). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Apr 29, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 30, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC22A5 c.1324_1325delinsAT (p.Ala442Ile) results in a non-conservative amino acid change in 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 3.8e-05 in 1614054 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (3.8e-05 vs 0.0046), allowing no conclusion about variant significance. c.1324_1325delinsAT has been reported in the literature in the homozygous and compound heterozygous states in individuals affected with Systemic Primary Carnitine Deficiency (e.g. Frigeni_2017, El-Hattab_2010, Ambroze_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that this variant causes reduced carnitine transport activity in vitro and in vivo (e.g. Frigeni_2017). The following publications have been ascertained in the context of this evaluation (PMID: 36109795, 20027113, 28841266). ClinVar contains an entry for this variant (Variation ID: 6428). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 23, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1324_1325delGCinsAT (p.A442I) alteration, located in coding exon 8 of the SLC22A5 gene, results from an in-frame deletion of GC and insertion of AT at nucleotide positions 1324 to 1325. This results in the substitution of the alanine residue for an isoleucine residue at codon 442. Based on data from gnomAD, the AT allele has an overall frequency of 0.0006% (3/282876) total alleles studied. The highest observed frequency was 0.002% (3/129190) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other SLC22A5 variants in individuals with features consistent with systemic primary carnitine deficiency; in at least one instance, the variants were identified in trans (Ambrose, 2022; El-Hattab, 2010; Frigeni, 2017). This amino acid position is well conserved in available vertebrate species. In an assay testing SLC22A5 function, this variant showed a functionally abnormal result (Frigeni, 2017). Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Mar 07, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect based on significantly reduced carnitine transport (PMID: 21922592); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20027113, 20574985, 21922592, 28841266) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607053; hg19: chr5-131728181;