5-132387065-C-T

Variant names:

• chr5-132387065-C-T
• rs386134212
• NM_003060.4:c.865C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_003060.4(SLC22A5):​c.865C>T​(p.Arg289*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,760 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 (★★). ClinVar reports functional evidence for this variant: "SCV001360661: The most pronounced variant effect results in <10% of normal carnitine transport activity in patient derived fibroblasts (example, Frigeni_2017).". Synonymous variant affecting the same amino acid position (i.e. R289R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.73
• 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001360661: The most pronounced variant effect results in <10% of normal carnitine transport activity in patient derived fibroblasts (example, Frigeni_2017).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132387065-C-T is Pathogenic according to our data. Variant chr5-132387065-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 25404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.865C>T	p.Arg289*	stop_gained	Exon 5 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.937C>T	p.Arg313*	stop_gained	Exon 6 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.865C>T	p.Arg289*	stop_gained	Exon 5 of 10	ENSP00000245407.3	O76082-1
	SLC22A5	ENST00000435065.7	TSL:1	c.937C>T	p.Arg313*	stop_gained	Exon 6 of 11	ENSP00000402760.2	O76082-3
	SLC22A5	ENST00000448810.6	TSL:1	n.865C>T		non_coding_transcript_exon	Exon 5 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251492 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461760 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 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: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111884

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000269 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Renal carnitine transport defect (7)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.28	N
PhyloP100		1.7
Vest4		0.96
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=7/193	disease causing (ClinVar)

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: rs386134212; hg19: chr5-131722757;