rs377767447

Variant names:

• chr5-132370203-GC-G
• rs377767447
• NM_003060.4:c.235delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003060.4(SLC22A5):​c.235delC​(p.His79ThrfsTer51) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000209 in 1,438,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.15
• Publications: 4 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132370203-GC-G is Pathogenic according to our data. Variant chr5-132370203-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 25359.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	c.235delC	p.His79ThrfsTer51	frameshift_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.235delC	p.His79ThrfsTer51	frameshift_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000101 AC: 2 AN: 198962 AF XY: 0.0000183

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: 0.00000209 AC: 3 AN: 1438802 Hom.: 0 Cov.: 31 AF XY: 0.00000420 AC XY: 3 AN XY: 713910

African (AFR) AF: 0.00 AC: 0 AN: 32960

American (AMR) AF: 0.00 AC: 0 AN: 41186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 38362

South Asian (SAS) AF: 0.0000356 AC: 3 AN: 84296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101154

Other (OTH) AF: 0.00 AC: 0 AN: 59410

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Pathogenic:3

Sep 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs377767447, gnomAD 0.007%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 25359). This variant is also known as c.232delC. This premature translational stop signal has been observed in individual(s) with primary carnitine deficiency (PMID: 16652335). This sequence change creates a premature translational stop signal (p.His79Thrfs*51) 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). -

Feb 19, 2021

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.235delC (p.His79ThrfsX51) 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 1e-05 in 198962 control chromosomes (gnomAD). c.235delC has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Amat di San Filippo_2006, Frigeni_2017). These data indicate that the variant may be associated with disease. Additionally, carnitine transport activity was measured in fibroblasts from one homozygous patient and the variant results in <10% of normal transport activity (Frigeni_2017). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs377767447; hg19: chr5-131705895;