5-132392577-G-T

Variant names:

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.1412G>T(p.Arg471Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,056 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. R471P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.57

Publications

10 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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr5-132392577-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1456659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 5-132392577-G-T is Pathogenic according to our data. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392577-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 956437.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.1412G>T	p.Arg471Leu	missense_variant	Exon 8 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.1412G>T	p.Arg471Leu	missense_variant	Exon 8 of 10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251434

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:2

Oct 03, 2022

Giacomini Lab, University of California, San Francisco

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:in vitro;research

- -

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 471 of the SLC22A5 protein (p.Arg471Leu). This variant is present in population databases (rs386134223, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SLC22A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 956437). 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.Arg471 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14605509, 25132046). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Pathogenic

4.2

H;.

PhyloP100

9.6

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.4

D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.79

Loss of methylation at R471 (P = 0.0129);.;

MVP

0.98

MPC

0.90

ClinPred

1.0

GERP RS

6.0

Varity_R

0.83

gMVP

0.95

Mutation Taster

=5/95

disease causing

(source)

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

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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