Submissions for variant NM_016955.4(SEPSECS):c.1276A>G (p.Thr426Ala)

gnomAD frequency: 0.00046  dbSNP: rs142133435

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000339643	SCV000449170	uncertain significance	Pontocerebellar hypoplasia type 2D	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001591008	SCV001825882	uncertain significance	not provided	2019-12-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001591008	SCV003492041	uncertain significance	not provided	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 426 of the SEPSECS protein (p.Thr426Ala). This variant is present in population databases (rs142133435, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SEPSECS-related conditions. ClinVar contains an entry for this variant (Variation ID: 348552). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002520234	SCV003704461	uncertain significance	Inborn genetic diseases	2024-02-05	criteria provided, single submitter	clinical testing	The c.1276A>G (p.T426A) alteration is located in exon 11 (coding exon 11) of the SEPSECS gene. This alteration results from a A to G substitution at nucleotide position 1276, causing the threonine (T) at amino acid position 426 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.