rs1554085861

Variant names:

• chr5-132369881-TGCCTGGTCGGCGGCGGGTGCCCCGCGCGCACGCGCAAAGCCCGCCGCGTTCCCCGACCCCAGGCCGCGCTCTGTGGGCCTCTGAGGGCGGCATGCGGGACTACGACGAGGTGA-T
• rs1554085861
• NM_003060.4:c.-91_22del

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_003060.4(SLC22A5):​c.-91_22del​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC22A5 NM_003060.4 frameshift, start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.03
• Publications: 2 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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 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 268 pathogenic variants in the truncated region.
• PP5: Variant 5-132369881-TGCCTGGTCGGCGGCGGGTGCCCCGCGCGCACGCGCAAAGCCCGCCGCGTTCCCCGACCCCAGGCCGCGCTCTGTGGGCCTCTGAGGGCGGCATGCGGGACTACGACGAGGTGA-T is Pathogenic according to our data. Variant chr5-132369881-TGCCTGGTCGGCGGCGGGTGCCCCGCGCGCACGCGCAAAGCCCGCCGCGTTCCCCGACCCCAGGCCGCGCTCTGTGGGCCTCTGAGGGCGGCATGCGGGACTACGACGAGGTGA-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 25341.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.-91_22del	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 10	ENST00000245407.8	NP_003051.1
SLC22A5	NM_003060.4	c.-91_22del		5_prime_UTR_variant	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	c.-91_22del	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3
SLC22A5	ENST00000245407.8	c.-91_22del		5_prime_UTR_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Renal carnitine transport defect Pathogenic:2

Jan 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 24, 2018

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC22A5 c.-91_22del113 deletes the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. The variant, c.-91_22del113, has been reported in the literature in two homozygous siblings affected with Systemic Primary Carnitine Deficiency, indicating that the variant may be associated with disease (Nezu_1999). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, though a submission prior to 2014 was reported as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=27/173	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554085861; hg19: chr5-131705573;