rs145068530

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

The NM_003060.4(SLC22A5):c.529A>G(p.Met177Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M177T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 0.937

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_003060.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-132384178-A-G is Pathogenic according to our data. Variant chr5-132384178-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 379230.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.05034238).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4 linkuse as main transcript	c.529A>G	p.Met177Val	missense_variant	3/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8 linkuse as main transcript	c.529A>G	p.Met177Val	missense_variant	3/10	1	NM_003060.4	P1	O76082-1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251486

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000269

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000646

Hom.:

Bravo

AF:

0.000340

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:3Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 177 of the SLC22A5 protein (p.Met177Val). This variant is present in population databases (rs145068530, gnomAD 0.1%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20574985). ClinVar contains an entry for this variant (Variation ID: 379230). 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, 36343260). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Nov 19, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	in vitro;research	Giacomini Lab, University of California, San Francisco	Oct 03, 2022	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2023

Functional analysis found p.(M177V) is associated with significantly impaired carnitine transport compared to wild-type (Frigeni et al., 2017); 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: 26828774, 20574985, 28841266, 36343260) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 17, 2022

Variant summary: SLC22A5 c.529A>G (p.Met177Val) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-05 in 282892 control chromosomes (gnomAD), predominantly at a frequency of 0.00088 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00088 vs 0.0046), allowing no conclusion about variant significance. c.529A>G has been reported in the literature in at least one compound heterozygous individuals affected with Systemic Primary Carnitine Deficiency (Li_2010). These data do not allow any conclusion about variant significance. Functional evidence obtained using stably transfected CHO cells demonstrated the variant had ~14% of normal activity (Frigeni_2017). Five ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and three as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;.

Eigen

Benign

-0.079

Eigen_PC

Benign

0.026

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.050

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.23

Sift

Benign

0.030

D;D;D

Sift4G

Benign

0.10

T;T;T

Polyphen

0.37

B;.;.

Vest4

0.59

MVP

0.60

MPC

0.23

ClinPred

0.85

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over