Submissions for variant NM_007103.4(NDUFV1):c.800G>A (p.Arg267Lys)

gnomAD frequency: 0.00010  dbSNP: rs141400889

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195680	SCV000251942	uncertain significance	not provided	2014-04-07	criteria provided, single submitter	clinical testing	p.Arg267Lys (AGA>AAA): c.800 G>A in exon 6 of the NDUFV1 gene (NM_007103.3). A variant of unknown significance has been identified in the NDUFV1 gene. The R267K missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R267K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a highly conserved position in the NDUFV1 protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether R267K is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Illumina Laboratory Services, Illumina	RCV000390228	SCV000373624	uncertain significance	Mitochondrial complex I deficiency, nuclear type 1	2018-01-13	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	RCV000294572	SCV000373625	uncertain significance	Leigh syndrome	2018-01-13	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.
Baylor Genetics	RCV000390228	SCV001526253	uncertain significance	Mitochondrial complex I deficiency, nuclear type 1	2018-04-11	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000195680	SCV002009516	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Invitae	RCV000195680	SCV002315246	uncertain significance	not provided	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 267 of the NDUFV1 protein (p.Arg267Lys). This variant is present in population databases (rs141400889, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NDUFV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 214857). 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 NDUFV1 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	RCV002517247	SCV003712488	uncertain significance	Inborn genetic diseases	2022-06-03	criteria provided, single submitter	clinical testing	The c.800G>A (p.R267K) alteration is located in exon 6 (coding exon 6) of the NDUFV1 gene. This alteration results from a G to A substitution at nucleotide position 800, causing the arginine (R) at amino acid position 267 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.