Submissions for variant NM_000387.6(SLC25A20):c.326+1del

dbSNP: rs757552268

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000389536	SCV000445212	pathogenic	Carnitine acylcarnitine translocase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	The SLC25A20 c.326+1delG variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in three studies in which it is found in a total of four individuals with carnitine-acylcarnitine translocase deficiency including in a homozygous state in two siblings and in a compound heterozygous state in two unrelated individuals (Yang et al. 2001; Hsu et al. 2001; Korman et al. 2006). The c.326+1delG variant was absent from 30 healthy controls and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in individual fibroblasts showed a total absence of CACT enzyme activity while RT-PCR analysis revealed the variant resulted in skipping of either exon 3 or both exon 3 and exon 4 in individual RNA (Yang et al. 2001; Hsu et al. 2001; Korman et al. 2006). Based on the collective evidence and potential impact of splice site variants, the c.326+1delG variant is classified as pathogenic for carnitine-acylcarnitine translocase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000478253	SCV000566377	pathogenic	not provided	2023-01-17	criteria provided, single submitter	clinical testing	Observed in trans with another variant in SLC25A20 in unrelated patients with SLC25A20-related carnitine-acylcarnitine translocase deficiency (Hsu et al., 2001; Korman et al., 2006); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32070364, 25614308, 33634872, 31589614, 36109795, 11592821, 11350184, 16919490)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000389536	SCV000918216	pathogenic	Carnitine acylcarnitine translocase deficiency	2018-10-05	criteria provided, single submitter	clinical testing	Variant summary: SLC25A20 c.326+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Five out five computational tools predict a significant impact on normal splicing consistent with multiple publications reporting experimental evidence that this variant affects mRNA splicing (Yang_2001, Hsu_2001). The variant allele was found at a frequency of 2.5e-05 in 244468 control chromosomes (gnomAD). c.326+1delG has been reported in the literature in multiple individuals affected with Carnitine-Acylcarnitine Translocase Deficiency (Yang_2001, Hsu_2001, Korman_2006), at-least one of whom was reported to have no Carnitine Acyltranslocase activity (Korman_2006). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000389536	SCV000946050	pathogenic	Carnitine acylcarnitine translocase deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (Splice site) in the SLC25A20 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A20 are known to be pathogenic (PMID: 25614308). This variant is present in population databases (rs757552268, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with carnitine-acylcarnitine translocase deficiency (PMID: 11350184, 11592821, 15365988, 16919490). This variant is also known as 388 1-G deletion and 326+1del. ClinVar contains an entry for this variant (Variation ID: 345943). 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.
Baylor Genetics	RCV000389536	SCV004201713	pathogenic	Carnitine acylcarnitine translocase deficiency	2024-02-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003972463	SCV004789609	pathogenic	SLC25A20-related disorder	2023-12-18	no assertion criteria provided	clinical testing	The SLC25A20 c.326+1delG variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in the homozygous or compound heterozygous state in clinically affected individuals with enzymatically or biochemically confirmed carnitine-acylcarnitine translocase (CACT) deficiency (Yang et al 2001. PubMed ID: 11350184, described as 388g deletion; Korman SH et al 2006. PubMed ID: 16919490; Bhattacharya K et al 2020. PubMed ID: 32070364). RNA studies have shown that the c.326+1del variant leads to aberrant splicing, primarily skipping of SLC25A20 exon 3 or exons 3 and 4 together (Yang et al 2001. PubMed ID: 11350184; Korman SH et al 2006. PubMed ID: 16919490). This variant is reported in 0.0080% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-48921428-AC-A). Taken together, this variant is interpreted as pathogenic.