rs72552722

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_003060.4(SLC22A5):c.12C>G(p.Tyr4*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,758 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.25

Publications

8 publications found

Variant links:

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 links:

MIR3936HG (HGNC:40538): (MIR3936 host gene)

MIR3936HG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 261 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-132369984-C-G is Pathogenic according to our data. Variant chr5-132369984-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 25347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4 link	c.12C>G	p.Tyr4*	stop_gained	Exon 1 of 10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 link	c.12C>G	p.Tyr4*	stop_gained	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248560

AF XY:

0.0000148

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460758

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111654

Other (OTH)

AF:

0.00

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:6

Mar 21, 2017

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 30, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC22A5 c.12C>G (p.Tyr4X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 248560 control chromosomes (gnomAD). c.12C>G has been reported in the literature in multiple homozygous individuals affected with Carnitine Deficiency and the variant segregated with the disease (examples: Wang_2001 and Frigeni_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Frigeni_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 22, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 25347). This premature translational stop signal has been observed in individual(s) with primary carnitine deficiency (PMID: 11715001). This variant is present in population databases (rs72552722, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Tyr4*) in the SLC22A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). -

SLC22A5-related disorder

Pathogenic:1

Sep 22, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC22A5 c.12C>G variant is predicted to result in premature protein termination (p.Tyr4*). This variant was reported in the homozygous state in individuals with primary carnitine deficiency (Wang et al 2001. PubMed ID: 11715001; Frigeni M et al 2017. PubMed ID: 28841266). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131705676-C-G). Nonsense variants in SLC22A5 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

PhyloP100

2.3

Vest4

0.73

GERP RS

5.0

PromoterAI

0.068

Neutral

(source)

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over