rs1554085861

Positions:

• chr5-132369881-TGCCTGGTCGGCGGCGGGTGCCCCGCGCGCACGCGCAAAGCCCGCCGCGTTCCCCGACCCCAGGCCGCGCTCTGTGGGCCTCTGAGGGCGGCATGCGGGACTACGACGAGGTGA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003060.4(SLC22A5):​c.-91_22del variant causes a start lost, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC22A5 NM_003060.4 start_lost, 5_prime_UTR
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.03

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

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 25341.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-132369881-TGCCTGGTCGGCGGCGGGTGCCCCGCGCGCACGCGCAAAGCCCGCCGCGTTCCCCGACCCCAGGCCGCGCTCTGTGGGCCTCTGAGGGCGGCATGCGGGACTACGACGAGGTGA-T is described in Lovd as [Pathogenic]. Variant chr5-132369881-TGCCTGGTCGGCGGCGGGTGCCCCGCGCGCACGCGCAAAGCCCGCCGCGTTCCCCGACCCCAGGCCGCGCTCTGTGGGCCTCTGAGGGCGGCATGCGGGACTACGACGAGGTGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.-91_22del		start_lost, 5_prime_UTR_variant	1/10	ENST00000245407.8
MIR3936HG	NR_110997.1			non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.-91_22del		start_lost, 5_prime_UTR_variant	1/10	1	NM_003060.4	P1
MIR3936HG	ENST00000621103.4			non_coding_transcript_exon_variant	1/8	1

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554085861; hg19: chr5-131705573;