ClinVar Miner

Submissions for variant NM_024120.5(NDUFAF5):c.836T>G (p.Met279Arg)

gnomAD frequency: 0.00002  dbSNP: rs761389904
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210569 SCV000262925 likely pathogenic Inborn genetic diseases 2013-09-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV000679869 SCV000807241 uncertain significance Mitochondrial complex I deficiency 2017-09-01 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory homozygous in a 13-year-old female with regression of motor skills, minor cognitive delays, hypotonia, restrictive lung disease, epilepsy, short stature, structural brain abnormalities, esotropia, hypertension
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001275555 SCV002103977 pathogenic Leigh syndrome 2022-02-24 criteria provided, single submitter clinical testing Variant summary: NDUFAF5 c.836T>G (p.Met279Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251314 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NDUFAF5 causing Leigh Syndrome (5.6e-05 vs 0.00056), allowing no conclusion about variant significance. c.836T>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple well characterized and comprehensively sequenced (by WES) individuals of East Asian ancestry affected with heterogeneous phenotypes of mitochondrial complex 1 assembly gene deficiency such as Leigh Syndrome, neurodevelopmental delay accompanied by unexplained dyspnea, lactic acidosis and Bilateral striatal necrosis (BSN) (example, Farwell_2015, Tong_2018, Simon_2019, Bi_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely Pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001507280 SCV002583273 pathogenic Mitochondrial complex 1 deficiency, nuclear type 16 criteria provided, single submitter clinical testing
Invitae RCV002517436 SCV003443417 pathogenic not provided 2024-01-03 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 279 of the NDUFAF5 protein (p.Met279Arg). This variant is present in population databases (rs761389904, gnomAD 0.09%). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 29581464, 30473481, 30581749, 34177781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225036). 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 NDUFAF5 protein function. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV001275555 SCV001460795 likely pathogenic Leigh syndrome 2020-09-16 no assertion criteria provided clinical testing
OMIM RCV001507280 SCV001712100 pathogenic Mitochondrial complex 1 deficiency, nuclear type 16 2023-10-11 no assertion criteria provided literature only

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