ClinVar Miner

Submissions for variant NM_002495.4(NDUFS4):c.462del (p.Lys154fs)

dbSNP: rs587776949
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197700 SCV000251900 pathogenic not provided 2023-02-24 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19107570, 24020637, 19364667, 22326555, 33233646, 33771987, 31589614, 20818383)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586784 SCV000697985 pathogenic Leigh syndrome 2016-08-18 criteria provided, single submitter clinical testing Variant summary: The NDUFS4 c.462delA (p.Lys154AsnfsX35) variant causes a frameshift mutation resulting in the elongation of the NDUFS4 protein by 12 amino acids. A functional study indicates that the mutation causes a reduction of the transcript levels by nonsense-mediated decay (NMD)(Assereto_2014). The variant of itnerest was observed in controls with an allele frequency of 14/131308, which does not exceed the estimated maximal expected allele frequency of a pathogenic NDUFS4 variant (0.00125). This variant has been reported in multiple LS patients both as homozygotes and compound heterozygotes. In addition, clinical diagnostic laboratory/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000197700 SCV003525825 pathogenic not provided 2023-12-22 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the NDUFS4 gene (p.Lys154Asnfs*35). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the NDUFS4 protein and extend the protein by 12 additional amino acid residues. This variant is present in population databases (rs773369163, gnomAD 0.02%). This frameshift has been observed in individuals with Leigh syndrome (PMID: 19107570, 19364667, 20818383, 24020637). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40257). Studies have shown that this frameshift alters NDUFS4 gene expression (PMID: 24020637). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002513319 SCV003745345 pathogenic Inborn genetic diseases 2021-04-20 criteria provided, single submitter clinical testing The c.462delA (p.K154Nfs*35) alteration, located in exon 5 (coding exon 5) of the NDUFS4 gene, consists of a deletion of one nucleotide at position 462, causing a translational frameshift with a predicted alternate stop codon after 35 amino acids. This alteration occurs at the 3' terminus of the NDUFS4 gene, is not expected to trigger nonsense-mediated mRNA decay and results in the elongation of the protein by 12 amino acids. This frameshift impacts the last 22 amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in multiple individuals with Leigh syndrome in the homozygous and compound heterozygous states (Anderson, 2008; Leshinsky-Silver, 2009; Calvo, 2010; Assereto, 2014). In one family, three affected siblings were homozygous and the parents and a healthy sibling were heterozygous (Anderson, 2008). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics RCV000133549 SCV004197756 pathogenic Mitochondrial complex I deficiency, nuclear type 1 2023-10-20 criteria provided, single submitter clinical testing
OMIM RCV000133549 SCV000057114 pathogenic Mitochondrial complex I deficiency, nuclear type 1 2014-07-01 no assertion criteria provided literature only

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