Submissions for variant NM_005005.3(NDUFB9):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00005  dbSNP: rs369824948

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000438795	SCV000516677	pathogenic	not provided	2015-04-22	criteria provided, single submitter	clinical testing	The c.1 A>G variant in the NDUFB9 gene has not been reported as a pathogenic variant. The substitution alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. We interpret c.1 A>G to be a pathogenic variant."
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222504	SCV002500269	uncertain significance	not specified	2024-02-09	criteria provided, single submitter	clinical testing	Variant summary: NDUFB9 c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met44) is located in exon 2 of the encoded protein. An activation of potential downstream translation at this initiation site would result in a shortened protein missing the first 43 amino acids from the protein sequence. To our knowledge no pathogenic variants have been reported upstream of this alternate codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251262 control chromosomes, predominantly at a frequency of 0.00029 within the Non-Finnish European subpopulation in the gnomAD database. This frequency does not allow for any conclusions about variant significance. To our knowledge, no occurrence of c.1A>G in individuals affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 24 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 379528). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000438795	SCV003286039	uncertain significance	not provided	2022-02-25	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the NDUFB9 mRNA. The next in-frame methionine is located at codon 44. This variant is present in population databases (rs369824948, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NDUFB9-related conditions. ClinVar contains an entry for this variant (Variation ID: 379528). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.