5-132392574-C-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_003060.4(SLC22A5):​c.1409C>A​(p.Ser470Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S470F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a transmembrane_region Helical; Name=11 (size 20) in uniprot entity OCTN2_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) 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-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 5-132392574-C-A is Pathogenic according to our data. Variant chr5-132392574-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2048266.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.1409C>A	p.Ser470Tyr	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>A	p.Ser470Tyr	missense_variant	Exon 8 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal carnitine transport defect Pathogenic:1

Nov 15, 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 tyrosine, which is neutral and polar, at codon 470 of the SLC22A5 protein (p.Ser470Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of primary carnitine deficiency (internal data). ClinVar contains an entry for this variant (Variation ID: 2048266). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC22A5 protein function with a positive predictive value of 95%. This variant disrupts the p.Ser470 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12210323). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.80		Loss of disorder (P = 0.0023);.;
MVP		0.98
MPC		0.92
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.81
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-131728266;