rs386134197

Variant names:

• chr5-132384206-T-C
• rs386134197
• NM_003060.4:c.557T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM1 PM2 PP5

The NM_003060.4(SLC22A5):​c.557T>C​(p.Leu186Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,276 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002124174: Experimental studies have shown that this missense change affects SLC22A5 function (PMID:28841266)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L186L) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 3.66
• Publications: 6 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet, G2P, ClinGen
• short QT syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002124174: Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266).; SCV003934857: The variant results in <2% of normal carnitine transport activity (e.g., Frigeni_2017, Koleske_2022). PMID: 32778825, 28841266, 36343260, 20574985
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 7 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132384206-T-C is Pathogenic according to our data. Variant chr5-132384206-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38287.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	NM_003060.4	MANE Select	c.557T>C	p.Leu186Pro	missense	Exon 3 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.629T>C	p.Leu210Pro	missense	Exon 4 of 11	NP_001295051.1	O76082-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.557T>C	p.Leu186Pro	missense	Exon 3 of 10	ENSP00000245407.3	O76082-1
	SLC22A5	ENST00000435065.7	TSL:1	c.629T>C	p.Leu210Pro	missense	Exon 4 of 11	ENSP00000402760.2	O76082-3
	SLC22A5	ENST00000448810.6	TSL:1	n.557T>C		non_coding_transcript_exon	Exon 3 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152276 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74398

African (AFR) AF: 0.0000241 AC: 1 AN: 41480

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	2	-	Renal carnitine transport defect (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.072	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.014	D
Sift4G	Benign	0.061	T
Polyphen		0.68	P
Vest4		0.93
MVP		0.94
MPC		0.92
ClinPred		0.92	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.92
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs386134197; hg19: chr5-131719898;