rs587776759

Positions:

• chr3-48857718-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000387.6(SLC25A20):​c.897_898insC​(p.Asn300GlnfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC25A20 NM_000387.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.415

Genes affected

SLC25A20 (HGNC:1421): (solute carrier family 25 member 20) This gene product is one of several closely related mitochondrial-membrane carrier proteins that shuttle substrates between cytosol and the intramitochondrial matrix space. This protein mediates the transport of acylcarnitines into mitochondrial matrix for their oxidation by the mitochondrial fatty acid-oxidation pathway. Mutations in this gene are associated with carnitine-acylcarnitine translocase deficiency, which can cause a variety of pathological conditions such as hypoglycemia, cardiac arrest, hepatomegaly, hepatic dysfunction and muscle weakness, and is usually lethal in new born and infants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 314 codons.
• PP5: Variant 3-48857718-T-TG is Pathogenic according to our data. Variant chr3-48857718-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 12132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A20	NM_000387.6	c.897_898insC	p.Asn300GlnfsTer24	frameshift_variant	9/9	ENST00000319017.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A20	ENST00000319017.5	c.897_898insC	p.Asn300GlnfsTer24	frameshift_variant	9/9	1	NM_000387.6	P1
SLC25A20	ENST00000430379.5	c.678_679insC	p.Asn227GlnfsTer24	frameshift_variant	7/7	3
SLC25A20	ENST00000479050.1	n.216_217insC		non_coding_transcript_exon_variant	2/2	2
SLC25A20	ENST00000440964.1	c.*727_*728insC		3_prime_UTR_variant, NMD_transcript_variant	10/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250746 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135638

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461714 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carnitine acylcarnitine translocase deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 16, 2023	This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this frameshift affects SLC25A20 function (PMID: 11162577). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 12132). This variant is also known as 955-959insC. This frameshift has been observed in individual(s) with carnitine-acylcarnitine translocase deficiency (PMID: 9399886; Invitae). This sequence change results in a frameshift in the SLC25A20 gene (p.Asn300Glnfs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the SLC25A20 protein and extend the protein by 21 additional amino acid residues. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 17, 2021	Variant summary: SLC25A20 c.897dupC (p.Asn300GlnfsX24) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4e-06 in 250746 control chromosomes. c.897dupC has been reported in the literature in at-least two homozygous individuals affected with Carnitine-Acylcarnitine Translocase Deficiency and subsequently cited by others (example, Huizing_1997, Wang_2011, Ijlst_2001, Costa_2003, Palmieri_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in non-detectable to 10% of normal carnitine acylcarnitine translocase (CACT) activity (example, Huizing_1997, IJlst_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776759; hg19: chr3-48895151;