Submissions for variant NM_007103.4(NDUFV1):c.1102G>A (p.Ala368Thr)

gnomAD frequency: 0.00006  dbSNP: rs376958800

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195640	SCV000251945	uncertain significance	not provided	2018-11-29	criteria provided, single submitter	clinical testing	p.Ala368Thr (GCC>ACC): c.1102 G>A in exon 8 of the NDUFV1 gene (NM_007103.3). A variant of unknown significance has been identified in the NDUFV1 gene. The A368T missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative in that a non-polar, smaller Alanine residue is replaced by a polar, larger Threonine residue. This change occurs at a highly conserved position in the NDUFV1 protein; however, multiple in-silico analysis programs predict that A368T is a benign sequence change. Therefore, based on the currently available information, it is unclear whether A368T is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Illumina Laboratory Services, Illumina	RCV000327027	SCV000373640	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.
Illumina Laboratory Services, Illumina	RCV000388550	SCV000373641	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195640	SCV002151678	uncertain significance	not provided	2025-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 368 of the NDUFV1 protein (p.Ala368Thr). This variant is present in population databases (rs376958800, gnomAD 0.2%). 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: 214860). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.