NM_003060.4:c.1085C>T

Variant names:

• chr5-132390722-C-T
• rs886042092
• NM_003060.4:c.1085C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PP3_Strong PP5

The NM_003060.4(SLC22A5):​c.1085C>T​(p.Ser362Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,848 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000756748: Experimental studies have shown that this missense change affects SLC22A5 function (PMID:36343260).". Synonymous variant affecting the same amino acid position (i.e. S362S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5
• Conservation: PhyloP100: 4.76
• Publications: 11 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000756748: Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 36343260).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 5-132390722-C-T is Pathogenic according to our data. Variant chr5-132390722-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281066.

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.1085C>T	p.Ser362Leu	missense	Exon 7 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.1157C>T	p.Ser386Leu	missense	Exon 8 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.1085C>T	p.Ser362Leu	missense	Exon 7 of 10	ENSP00000245407.3	O76082-1
	SLC22A5	ENST00000435065.7	TSL:1	c.1157C>T	p.Ser386Leu	missense	Exon 8 of 11	ENSP00000402760.2	O76082-3
	SLC22A5	ENST00000448810.6	TSL:1	n.1053-54C>T		intron	N/A	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33476

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: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	3	-	Renal carnitine transport defect (6)
-	1	-	Decreased circulating carnitine concentration (1)
1	-	-	Dilated cardiomyopathy 1A (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.88		Loss of catalytic residue at S362 (P = 0.1439)
MVP		0.95
MPC		0.71
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.69
gMVP		0.76
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs886042092; hg19: chr5-131726414; COSMIC: COSV55373865; COSMIC: COSV55373865;