NM_003060.4:c.83G>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_003060.4(SLC22A5):c.83G>T(p.Ser28Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,020 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. S28R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.01

Publications

7 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 links:

MIR3936HG (HGNC:40538): (MIR3936 host gene)

MIR3936HG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_003060.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-132370056-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1472873.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 5-132370055-G-T is Pathogenic according to our data. Variant chr5-132370055-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 25354.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.83G>T	p.Ser28Ile	missense_variant	Exon 1 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.83G>T	p.Ser28Ile	missense_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

249026

AF XY:

0.00

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:

0.00000205

AC:

AN:

1461020

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726864

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52992

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111730

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:3

Jul 15, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 28, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine with isoleucine at codon 28 of the SLC22A5 protein (p.Ser28Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in individuals affected with primary carnitine deficiency (PMID: 12408185, 23379544). ClinVar contains an entry for this variant (Variation ID: 25354). This variant has been reported to affect SLC22A5 protein function (PMID: 28841266). 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. For these reasons, this variant has been classified as Pathogenic. -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC22A5-related disorder

Pathogenic:1

May 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SLC22A5 c.83G>T variant is predicted to result in the amino acid substitution p.Ser28Ile. This variant has been reported in individuals with systemic primary carnitine deficiency, and functional studies support its pathogenicity (Rahbeeni et al. 2002. PubMed ID: 12408185; Frigeni et al. 2017. PubMed ID: 28841266). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Jan 27, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional studies of the p.(S28I) variant show significantly decreased transport activity compared to cells expressing the wildtype genotype (PMID: 28841266); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23379544, 16652335, 26828774, 12408185, 16602102, 28841266) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.8

L;L

PhyloP100

4.0

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.82

Sift

Benign

0.082

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.95

P;.

Vest4

0.90

MutPred

0.82

Loss of catalytic residue at S28 (P = 0.1623);Loss of catalytic residue at S28 (P = 0.1623);

MVP

0.95

MPC

0.37

ClinPred

0.96

GERP RS

5.2

PromoterAI

0.30

Neutral

(source)

Varity_R

0.63

gMVP

0.93

Mutation Taster

=0/100

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

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NM_003060.4:c.83G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over