3-48859097-T-C

Variant names:

• chr3-48859097-T-C
• rs28934589
• NM_000387.6:c.713A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000387.6(SLC25A20):​c.713A>G​(p.Gln238Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A20 NM_000387.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.00
• Publications: 13 publications found

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]

PRKAR2A-AS1 (HGNC:40471): (PRKAR2A antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000387.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-48859097-T-C is Pathogenic according to our data. Variant chr3-48859097-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12138.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
SLC25A20	NM_000387.6	c.713A>G	p.Gln238Arg	missense_variant	Exon 7 of 9	ENST00000319017.5	NP_000378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A20	ENST00000319017.5	c.713A>G	p.Gln238Arg	missense_variant	Exon 7 of 9	1	NM_000387.6	ENSP00000326305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00184 Hom.: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carnitine acylcarnitine translocase deficiency Pathogenic:4

Apr 15, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC25A20 c.713A>G (p.Gln238Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250762 control chromosomes. c.713A>G has been reported in the literature in multiple individuals affected with Carnitine-Acylcarnitine Translocase Deficiency (e.g. Al Aqeel_2003, Galron_2004, Iacobazzi_2004). These data indicate that the variant is very likely to be associated with disease. Additionally, at least two publications report that the variant results in enzyme activities <5% of normal in fibroblasts from homozygous patients (e.g. Al Aqeel_2003, Iacobazzi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 12859414, 15159657, 15057979). ClinVar contains an entry for this variant (Variation ID: 12138). Based on the evidence outlined above, the variant was classified as pathogenic. -

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Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Compatible metabolite assay -

not provided Pathogenic:1

Dec 17, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.7	.;H
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.93		.;Gain of methylation at Q238 (P = 0.0145);
MVP		1.0
MPC		0.98
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs28934589; hg19: chr3-48896530;