5-132392574-C-T

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.1409C>T​(p.Ser470Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,870 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. S470Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

10
8
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 7.54

Publications

8 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

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 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr5-132392574-C-A is described in CliVar as Pathogenic. Clinvar id is 2048266.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 5-132392574-C-T is Pathogenic according to our data. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132392574-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 25425.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
SLC22A5NM_003060.4 linkc.1409C>T p.Ser470Phe 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
SLC22A5ENST00000245407.8 linkc.1409C>T p.Ser470Phe missense_variant Exon 8 of 10 1 NM_003060.4 ENSP00000245407.3 O76082-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000795
AC:
2
AN:
251466
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461870
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727234
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112002
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32
Alfa
AF:
0.00000499
Hom.:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Renal carnitine transport defect Pathogenic:7Uncertain:1
-
CENTOGENE GmbH and LLC - Guiding Precision Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 15, 2021
Genome-Nilou Lab
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 04, 2022
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 15, 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.1409C>T (p.Ser470Phe) 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 allele was found at a frequency of 8e-06 in 251466 control chromosomes. c.1409C>T has been reported in the literature in the homozygous state in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Cheema_2020, ALghamdi_2018, Lamhonwah_2002). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in CHO cells reports experimental evidence that this variant results in 0 transport activity compared to wildtype (e.g. Frigeni_2017). This variant is also known as c.1481C>T(p.Ser494Phe). The following publications have been ascertained in the context of this evaluation (PMID: 30069296, 33083013, 28841266, 12210323). ClinVar contains an entry for this variant (Variation ID: 25425). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 03, 2022
Giacomini Lab, University of California, San Francisco
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:in vitro;research

- -

May 03, 2018
Counsyl
Significance:Uncertain significance
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. -

May 18, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 470 of the SLC22A5 protein (p.Ser470Phe). This variant is present in population databases (rs386134222, gnomAD 0.006%). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 12210323). ClinVar contains an entry for this variant (Variation ID: 25425). 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: 28841266). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2
Feb 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 19, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.47
D
MutationAssessor
Pathogenic
3.5
M;.
PhyloP100
7.5
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.013
D;D
Polyphen
1.0
D;.
Vest4
0.81
MutPred
0.90
Loss of disorder (P = 2e-04);.;
MVP
0.98
MPC
0.84
ClinPred
0.97
D
GERP RS
6.0
Varity_R
0.83
gMVP
0.96
Mutation Taster
=5/95
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386134222; hg19: chr5-131728266; API