ClinVar Miner

Submissions for variant NM_002490.6(NDUFA6):c.309del (p.Met104fs)

dbSNP: rs763006208
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002532030 SCV003718917 likely pathogenic Inborn genetic diseases 2022-01-20 criteria provided, single submitter clinical testing The c.387delT (p.M130Cfs*35) alteration, located in exon 3 (coding exon 3) of the NDUFA6 gene, consists of a deletion of one nucleotide at position 387, causing a translational frameshift with a predicted alternate stop codon after 35 amino acids. This alteration occurs at the 3' terminus of the NDUFA6 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 15% of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the c.387delT allele has an overall frequency of 0.01% (16/282896) total alleles studied. The highest observed frequency was 0.01% (16/129192) of European (non-Finnish) alleles. This variant, designated as 309del was confirmed in trans with a second NDUFA6 frameshift variant in an infant presenting with unusual movements suggestive of seizure disorder, elevated blood gas lactate, abnormal brain MRI with white matter changes, and deterioration as a result of status epilepticus, apnea episodes, and persistent lactic acidosis (Alston, 2018). Based on the available evidence, this alteration is classified as likely pathogenic.
Wellcome Centre for Mitochondrial Research, Newcastle University RCV000680373 SCV000787626 pathogenic Mitochondrial disease 2018-07-19 no assertion criteria provided clinical testing
OMIM RCV000710001 SCV000840366 pathogenic Mitochondrial complex 1 deficiency, nuclear type 33 2018-12-13 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004758045 SCV005344955 pathogenic NDUFA6-related disorder 2024-09-17 no assertion criteria provided clinical testing The NDUFA6 c.387delT variant is predicted to result in a frameshift and premature protein termination (p.Met130Cysfs*35). This variant , also designated c.309del (p.Met104Cysfs*35) in an alternate transcript, has been reported in compound heterozygous states individuals with mitochondrial complex I deficiency (Alston et al. 2018. PubMed ID: 30245030; Table S3, French et al. 2022. PubMed ID: 35586607). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in NDUFA6 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.

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