Submissions for variant NM_014251.3(SLC25A13):c.1638_1660dup (p.Ala554fs)

gnomAD frequency: 0.00001  dbSNP: rs80338725

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726889	SCV000703906	pathogenic	not provided	2016-11-18	criteria provided, single submitter	clinical testing
Invitae	RCV000822371	SCV000963171	pathogenic	Citrin deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala554Glyfs*17) in the SLC25A13 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A13 are known to be pathogenic (PMID: 10369257, 14680984, 27405544). This variant is present in population databases (rs80338725, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with SLC25A13-related conditions (PMID: 27405544). ClinVar contains an entry for this variant (Variation ID: 6003). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004526	SCV001163572	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726889	SCV002020659	pathogenic	not provided	2021-05-10	criteria provided, single submitter	clinical testing
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	RCV001004526	SCV002546529	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency	2022-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006371	SCV003845174	pathogenic	Citrullinemia type II	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: SLC25A13 c.1638_1660dup23 (p.Ala554GlyfsX17) 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 within ClinVar (e.g. c.1799dup [p.Tyr600Ter], c.1813C>T [p.Arg605Ter]). The variant allele was found at a frequency of 8.8e-05 in 251412 control chromosomes (gnomAD), predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SLC25A13 causing Citrullinemia Type II (8.8e-05 vs 0.0012), allowing no conclusion about variant significance. c.1638_1660dup23 has been reported in the literature as a biallelic genotype in multiple individuals affected with Citrullinemia (e.g. Song_2011, Wang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV002259302	SCV004203613	pathogenic	Citrullinemia, type II, adult-onset	2023-10-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000726889	SCV004226563	pathogenic	not provided	2022-08-11	criteria provided, single submitter	clinical testing	PM2, PM3_strong, PVS1
OMIM	RCV000006371	SCV000026553	pathogenic	Citrullinemia type II	1999-06-01	no assertion criteria provided	literature only
GeneReviews	RCV002259302	SCV000041254	not provided	Citrullinemia, type II, adult-onset		no assertion provided	literature only
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV001004526	SCV004800859	pathogenic	Neonatal intrahepatic cholestasis due to citrin deficiency		no assertion criteria provided	clinical testing	PVS1+PM3_VS+PP4