rs121908889

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_003060.4(SLC22A5):c.506G>A(p.Arg169Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,078 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. R169W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.20

Publications

22 publications found

Variant links:

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

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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, 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 chr5-132384154-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 5-132384155-G-A is Pathogenic according to our data. Variant chr5-132384155-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6421.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 link	c.506G>A	p.Arg169Gln	missense_variant	Exon 3 of 10	ENST00000245407.8	NP_003051.1	O76082-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 link	c.506G>A	p.Arg169Gln	missense_variant	Exon 3 of 10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000437

AC:

AN:

251434

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000582

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:10

Jun 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the SLC22A5 protein (p.Arg169Gln). This variant is present in population databases (rs121908889, gnomAD 0.02%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 10425211, 20574985, 21922592, 23090741, 26828774). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6421). 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%. This variant disrupts the p.Arg169 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11058897, 12210323, 23090741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Mar 07, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The SLC22A5 c.506G>A (p.R169Q) missense variant has been reported in the homozygous and compound heterozygous state in individuals with systemic primary carnitine deficiency (PMID: 10425211; 21922592; 23090741; 20574985). -

Jul 15, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 10, 2018

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.506G>A (p.Arg169Gln) results in a conservative amino acid change that affects a highly conserved sequence motif in the encoded protein sequence (Burwinkel 1999). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 246204 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (4.5e-05 vs 0.0046), allowing no conclusion about variant significance. c.506G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Burwinkel 1999, Rose 2012, Yoon 2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Rose 2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 27, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 02, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Sep 25, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional analysis of R169Q found that it is associated with significantly reduced carnitine transport compared to wild-type (Frigeni et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10425211, 20574985, 23090741, 21922592, 26828774, 28841266, 34178604, 33560599, 32853555) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;.;.

PhyloP100

9.2

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.98

MutPred

0.97

Loss of MoRF binding (P = 0.0627);.;.;

MVP

0.99

MPC

0.87

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.95

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over