Submissions for variant NM_174889.5(NDUFAF2):c.131A>C (p.Gln44Pro)

gnomAD frequency: 0.00007  dbSNP: rs775605330

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197862	SCV000251821	likely pathogenic	not provided	2014-05-06	criteria provided, single submitter	clinical testing	p.Gln44Pro (CAA>CCA): c.131 A>C in exon 2 of the NDUFAF2 gene (NM_174889.4). The Q44P variant that is likely pathogenic in the NDUFAF2 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Q44P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).
Illumina Laboratory Services, Illumina	RCV001157922	SCV001319528	uncertain significance	Leigh syndrome	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.
Illumina Laboratory Services, Illumina	RCV001157923	SCV001319529	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197862	SCV002126019	uncertain significance	not provided	2022-06-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 44 of the NDUFAF2 protein (p.Gln44Pro). This variant is present in population databases (rs775605330, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with NDUFAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214740). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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	RCV002515408	SCV003688123	uncertain significance	Inborn genetic diseases	2021-06-29	criteria provided, single submitter	clinical testing	The c.131A>C (p.Q44P) alteration is located in exon 2 (coding exon 2) of the NDUFAF2 gene. This alteration results from a A to C substitution at nucleotide position 131, causing the glutamine (Q) at amino acid position 44 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.