rs72552734

Positions:

• chr5-132392519-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_003060.4(SLC22A5):​c.1354G>A​(p.Glu452Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 9.57

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 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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, 0.982
• PP5: Variant 5-132392519-G-A is Pathogenic according to our data. Variant chr5-132392519-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25421.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=3, Uncertain_significance=1}. Variant chr5-132392519-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.1354G>A	p.Glu452Lys	missense_variant	8/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.1354G>A	p.Glu452Lys	missense_variant	8/10	1	NM_003060.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251480 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135908

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461754 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000307 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Renal carnitine transport defect Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 452 of the SLC22A5 protein (p.Glu452Lys). This variant is present in population databases (rs72552734, gnomAD 0.01%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 10679939, 20574985, 27581592). ClinVar contains an entry for this variant (Variation ID: 25421). 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: 10679939). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2020	Variant summary: SLC22A5 c.1354G>A (p.Glu452Lys) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251480 control chromosomes. c.1354G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (example, Li_2010, Deswal_2017, Frigeni_2017, Wang_2000). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example Frigeni_2017, Wang_2000). The most pronounced variant effect results in <10% of normal carnitine transport activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories have recently classified/re-classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 13, 2014	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	SLC22A5: PP4:Strong, PM2, PM3, PP3, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.92		Gain of methylation at E452 (P = 0.0203);.;
MVP		1.0
MPC		0.86
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.98
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

LitVar

Other links and lift over

dbSNP: rs72552734; hg19: chr5-131728211; COSMIC: COSV55374456; COSMIC: COSV55374456;