Submissions for variant NM_007103.4(NDUFV1):c.1080G>A (p.Ser360=)

gnomAD frequency: 0.00002  dbSNP: rs201992354

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
The Molecular Genetic and Pathologic Diagnosis Center of Neuromuscular Disorder, Children's Hospital of Fudan University	RCV001249206	SCV001422460	likely pathogenic	Leigh syndrome	2019-12-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001267713	SCV001445965	uncertain significance	Mitochondrial complex I deficiency	2020-11-16	criteria provided, single submitter	curation	The heterozygous p.Ser360= variant in NDUFV1 was identified by our study along with another variant in 1 individual with mitochondrial complex I deficiency, nuclear type 4. Trio genome analysis revealed that this variant was in trans with another variant of uncertain significance. This variant has been reported in 2 individuals, one with unknown affected status and one with mitochondrial complex I deficiency, nuclear type 4 (PMID: 31687339, 32348839), both of which were compound heterozygotes that carried variants of uncertain significance in trans (VariationID: 496918; PMID: 32348839). The p.Ser360= variant has been identified in 0.005% (6/116856) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201992354). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (variation ID#: 972920) and has been interpreted as likely pathogenic by the Molecular Genetic and Pathologic Diagnosis Center of Neuromuscular Disorder (Children's Hospital of Fudan University). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001879751	SCV002296769	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects codon 360 of the NDUFV1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NDUFV1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201992354, gnomAD 0.005%). This variant has been observed in individual(s) with clinical features of NDUFV1-related conditions (PMID: 24642831, 32348839, 34740920). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 972920). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 31687339, 32123317). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249206	SCV005886890	likely pathogenic	Leigh syndrome	2025-01-28	criteria provided, single submitter	clinical testing	Variant summary: NDUFV1 c.1080G>A (p.Ser360Ser) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes or weakens a 5' donor site. Multiple publications report experimental evidence that this variant affects mRNA splicing, creating a p.(Gly305AspfsTer12) change resulting in a premature termination codon (e.g. Wai_2020, Yamada_2019, Kiss_2023). The variant allele was found at a frequency of 3.5e-05 in 226246 control chromosomes. c.1080G>A has been reported in the literature in compound heterozygous individuals affected with mitochondrial disease including Mitochondrial complex I deficiency and mitochondrial encephalopathy (e.g. Cloney_2022, Hu_2020, Nesbitt_2014, Kiss_2023). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34740920, 32348839, 36896486, 24642831, 32123317, 31687339). ClinVar contains an entry for this variant (Variation ID: 972920). Based on the evidence outlined above, the variant was classified as likely pathogenic.