Submissions for variant NM_014251.3(SLC25A13):c.1420G>A (p.Val474Met)

dbSNP: rs554809009

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241944	SCV001415000	uncertain significance	Citrin deficiency	2022-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 474 of the SLC25A13 protein (p.Val474Met). This variant is present in population databases (rs554809009, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SLC25A13-related conditions. ClinVar contains an entry for this variant (Variation ID: 967116). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC25A13 protein function. Experimental studies have shown that this missense change affects SLC25A13 function (PMID: 25110155). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001578819	SCV001806148	uncertain significance	Citrullinemia, type II, adult-onset	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001578820	SCV001806149	uncertain significance	Neonatal intrahepatic cholestasis due to citrin deficiency	2021-07-22	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003238329	SCV002010680	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Mendelics	RCV002246229	SCV002519366	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002246229	SCV004804458	uncertain significance	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: SLC25A13 c.1420G>A (p.Val474Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251460 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC25A13 causing Citrullinemia Type II (0.0001 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1420G>A in individuals affected with Citrullinemia Type II has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Zhang_2014). The most pronounced variant effect results in 30%-50% of normal activity in an in vitro yeast model. The following publication has been ascertained in the context of this evaluation (PMID: 25110155). ClinVar contains an entry for this variant (Variation ID: 967116). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV001835116	SCV002079374	uncertain significance	Citrullinemia	2020-03-19	no assertion criteria provided	clinical testing