rs760320629

chr5-132385493-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_003060.4(SLC22A5):c.818T>C(p.Leu273Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,810 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 (★). Synonymous variant affecting the same amino acid position (i.e. L273L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.11

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 5-132385493-T-C is Pathogenic according to our data. Variant chr5-132385493-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 460417.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.818T>C	p.Leu273Pro	missense_variant	4/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.818T>C	p.Leu273Pro	missense_variant	4/10	1	NM_003060.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251394 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135890

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 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: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal carnitine transport defect Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2023

This missense change has been observed in individual(s) with primary carnitine deficiency (Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 460417). This variant is present in population databases (rs760320629, gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 273 of the SLC22A5 protein (p.Leu273Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.72		Loss of catalytic residue at L273 (P = 0.0046);.;.;
MVP		0.98
MPC		1.0
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.95

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

Other links and lift over

dbSNP: rs760320629; hg19: chr5-131721185;