Submissions for variant NM_016013.4(NDUFAF1):c.249T>A (p.Asp83Glu)

gnomAD frequency: 0.00015  dbSNP: rs146540015

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198494	SCV000251810	uncertain significance	not provided	2018-06-04	criteria provided, single submitter	clinical testing	The variant is found in MITONUC-MITOP panel(s).
Illumina Laboratory Services, Illumina	RCV001116067	SCV001274093	uncertain significance	Mitochondrial complex I deficiency, nuclear type 1	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.
Invitae	RCV000198494	SCV002247873	uncertain significance	not provided	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 83 of the NDUFAF1 protein (p.Asp83Glu). This variant is present in population databases (rs146540015, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NDUFAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 214730). 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 NDUFAF1 protein function with a negative predictive value of 80%. 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	RCV002517237	SCV003717565	uncertain significance	Inborn genetic diseases	2022-08-02	criteria provided, single submitter	clinical testing	The c.249T>A (p.D83E) alteration is located in exon 2 (coding exon 1) of the NDUFAF1 gene. This alteration results from a T to A substitution at nucleotide position 249, causing the aspartic acid (D) at amino acid position 83 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.