NM_003060.4:c.1409C>T

Variant names:

• chr5-132392574-C-T
• rs386134222
• NM_003060.4:c.1409C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1
• Conservation: PhyloP100: 7.54
• Publications: 8 publications found

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

ACMG classification

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
SLC22A5	NM_003060.4	c.1409C>T	p.Ser470Phe	missense_variant	Exon 8 of 10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.1409C>T	p.Ser470Phe	missense_variant	Exon 8 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251466 AF XY: 0.00000736

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

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000499 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:7 Uncertain: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

Other links and lift over

dbSNP: rs386134222; hg19: chr5-131728266;