Submissions for variant NM_005002.5(NDUFA9):c.224G>T (p.Arg75Leu)

dbSNP: rs35263902

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203115	SCV000258011	uncertain significance	not specified	2015-03-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000988772	SCV001138629	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 26	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000200129	SCV002402753	benign	not provided	2023-10-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000988772	SCV002769460	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 26	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_005002.4(NDUFA9):c.224G>T in exon 3 of 11 of the NDUFA9 gene. This substitution is predicted to create a major amino acid change from arginine to leucine at position 75 of the protein, NP_004993.1(NDUFA9):p.(Arg75Leu). The arginine at this position has moderate conservation (100 vertebrates, UCSC), and is located within the epimerase functional domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.075% (207 heterozygotes, 2 homozygotes). An alternative residue change at the same location has been reported in the gnomAD database at a frequency of 0.086%. The variant has been previously reported as both a VUS and as likely pathogenic (ClinVar). A different variant in the same codon resulting in a changes to cysteine has been described as a VUS (LOVD). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Revvity Omics, Revvity	RCV000988772	SCV003813519	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 26	2019-07-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000200129	SCV000251802	likely pathogenic	not provided	2014-05-02	flagged submission	clinical testing	p.Arg75Leu (CGC>CTC): c.224 G>T in exon 3 of the NDUFA9 gene (NM_005002.4). The R75L variant that is likely pathogenic was identified in the NDUFA9 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R75L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).