5-132384302-G-A

Variant names:

• chr5-132384302-G-A
• rs386134200
• NM_003060.4:c.652+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003060.4(SLC22A5):​c.652+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.20
• Publications: 4 publications found

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]

SLC22A5 Gene-Disease associations (from GenCC):

• systemic primary carnitine deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• short QT syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.6, offset of 13, new splice context is: cagGTtgga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132384302-G-A is Pathogenic according to our data. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132384302-G-A is described in CliVar as Pathogenic. Clinvar id is 25381.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.652+1G>A		splice_donor_variant, intron_variant	Intron 3 of 9	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.652+1G>A		splice_donor_variant, intron_variant	Intron 3 of 9	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251494 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111906

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000366 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:6

Jun 06, 2019

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.652+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251494 control chromosomes (gnomAD). c.652+1G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Lamhonwah_2002, Hwu_2007, Frigeni_2017). These data indicate that the variant may be associated with disease. Two compound heterozygote patients were found to have significantly lower carnitine uptake/levels (Lamhonwah_2002, Hwu_2007). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. 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 31, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 3 of the SLC22A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). This variant is present in population databases (rs386134200, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with primary carnitine deficiency (PMID: 12210323). ClinVar contains an entry for this variant (Variation ID: 25381). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects SLC22A5 function (PMID: 2235122, 12210323). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Decreased circulating carnitine concentration Pathogenic:1

Mar 31, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 19, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26828774, 28841266, 16602102, 17703373, 12210323) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.2
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: 18
DS_DL_spliceai		0.93		Position offset: -1

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

Other links and lift over

dbSNP: rs386134200; hg19: chr5-131719994;