Submissions for variant NM_007103.4(NDUFV1):c.640G>A (p.Glu214Lys)

gnomAD frequency: 0.00001  dbSNP: rs121913661

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497761	SCV000589486	pathogenic	not provided	2022-06-15	criteria provided, single submitter	clinical testing	Functional studies suggest the E214K variant has impaired complex I activity when expressed in Y. lipolytica (Varghese et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11494300, 22142868, 26345448, 16120313, 23334465, 27344648, 11349233, 32871395, 34807224, 33258288, 33807701)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234905	SCV003933871	pathogenic	Leigh syndrome	2023-05-26	criteria provided, single submitter	clinical testing	Variant summary: NDUFV1 c.640G>A (p.Glu214Lys) results in a conservative amino acid change located in the FMN-binding domain (IPR011538) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251482 control chromosomes (gnomAD). c.640G>A has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with complex I deficiency related phenotypes, including Leigh Syndrome (e.g. Benit_2001, Lal_2013, Quaio_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased complex I activity, together with increased reactive oxygen species production in a yeast model system (Varghese_2015). The following publications have been ascertained in the context of this evaluation (PMID: 11349233, 23334465, 33258288, 26345448). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000497761	SCV004294894	pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	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) has been performed at Invitae 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. Experimental studies have shown that this missense change affects NDUFV1 function (PMID: 26345448). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 14059). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 214 of the NDUFV1 protein (p.Glu214Lys). This variant is present in population databases (rs121913661, gnomAD 0.007%). This missense change has been observed in individual(s) with Leigh syndrome and/or mitochondrial complex I deficiency (PMID: 11349233, 23334465, 27344648, 33258288, 34807224). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals.
OMIM	RCV000015103	SCV000035360	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 4	2001-06-01	no assertion criteria provided	literature only