Submissions for variant NM_000387.6(SLC25A20):c.199-10T>G

gnomAD frequency: 0.00003  dbSNP: rs541208710

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427395	SCV000515900	pathogenic	not provided	2021-11-18	criteria provided, single submitter	clinical testing	Reverse transcriptase PCR in patient fibroblasts indicate c.199-10 T>G results in abnormal gene splicing (Ogawa et al., 2000); This variant is associated with the following publications: (PMID: 25459972, 29137068, 10697964, 15363639, 11592821, 29996190, 31108048, 31965297, 31501239, 32411386, 33634872, 33194920, 32778825, 24088670)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012920	SCV000632619	pathogenic	Carnitine acylcarnitine translocase deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the SLC25A20 gene. It does not directly change the encoded amino acid sequence of the SLC25A20 protein. This variant is present in population databases (rs541208710, gnomAD 0.09%). This variant has been observed in individuals with carnitine–acylcarnitine translocase deficiency (PMID: 10697964, 24088670, 25459972, 26238931, 27066551). It has also been observed to segregate with disease in related individuals. This variant is also known as 261-10T>G. ClinVar contains an entry for this variant (Variation ID: 12137). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012920	SCV000696660	pathogenic	Carnitine acylcarnitine translocase deficiency	2017-01-06	criteria provided, single submitter	clinical testing	Variant summary: The SLC25A20 c.199-10T>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict the creation or enhancement of a cryptic splice donor site along with the weakening of a canonical splicing acceptor site. Functional studies have shown the patients with this variant in compound heterozygosity had exon 3/4 skipping, and abberant splicing was also observed in patients and parents who had coding variants suggesting coding sequence mutations might contribute to the presence of aberrantly spliced mRNA (Hsu_2001). The variant was found in numerous affected individuals both in the homozygous and heterozygous state, and the variant has been suggested as an Asian founder mutation. This variant was found in 4/121236 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC25A20 variant (0.001118). In addition, one reputable clinical diagnostic laboratory/multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000012920	SCV001190562	pathogenic	Carnitine acylcarnitine translocase deficiency	2019-05-10	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000012920	SCV002556627	pathogenic	Carnitine acylcarnitine translocase deficiency	2020-03-26	criteria provided, single submitter	clinical testing	The SLC25A20:c.199-10T>G variant is a single nucleotide substitution which results in aberrant splicing. The variant has been reported in the literature as homozygous or heterozygous in combination with another SLC25A20 variant in affected patients (PMID: 25459972, PMID: 25459972) . It has been described as a founder mutation in East Asian populations. RNA studies demonstrate exon 3 and exon 3/4 skipping which is predicted to be detrimental to protein function (PMID: 10697964). It is present in population databases at 0.007% (20 het/280674 allele count) (PP). Splice prediction programs in Alamut indicate that the variant may disrupt the exon 3 acceptor site. The variant is described in ClinVar as pathogenic and HGMD (2019.4) as disease causing (PP5).
Baylor Genetics	RCV000012920	SCV004201707	pathogenic	Carnitine acylcarnitine translocase deficiency	2024-03-27	criteria provided, single submitter	clinical testing
OMIM	RCV000012920	SCV000033161	pathogenic	Carnitine acylcarnitine translocase deficiency	2013-12-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004757104	SCV005358930	pathogenic	SLC25A20-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The SLC25A20 c.199-10T>G variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous and homozygous state in multiple patients with autosomal recessive carnitine-acylcarnitine translocase deficiency (Ogawa et al. 2000. PubMed ID: 10697964, Tang et al. 2019. PubMed ID: 31108048, Vatanavicharn et al. 2015. PubMed ID: 25459972). RNA studies showed that this variant leads to aberrant splicing and truncation of the protein (Ogawa et al. 2000. PubMed ID: 10697964). This variant is reported in 0.095% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.