ClinVar Miner

Submissions for variant NM_002495.4(NDUFS4):c.462del (p.Lys154fs) (rs587776949)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197700 SCV000251900 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing p.Lys154AsnfsX35: c.462delA in exon 5 of the NDUFS4 gene (NM_002495.2). The c.462delA variant in the NDUFS4 gene has been reported previously in association with autosomal recessive Leigh syndrome when present in the homozygous state or when in trans with another disease-causing variant (Anderson et al., 2008; Calvo et al., 2010; Assereto et al., 2014). The c.462delA variant causes a frameshift starting with codon Lysine 154, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 35 of the new reading frame, denoted p.Lys154AsnfsX35. This variant is predicted to replace the last 22 amino acids of the protein with 34 incorrect amino acids, resulting in an NDUFS4 protein that lacks a cAMP-dependent protein kinase phosphorylation site required for activation of mitochondrial respiratory chain complex I (Anderson et al., 2008). In addition, functional studies demonstrated lack of protein in fibroblasts and mitochondria from affected individuals with the c.462delA variant (Calvo et al., 2010; Assereto et al., 2014). The c.462delA variant is observed in 17/245,512 global alleles in large population cohorts, with no homozygous individuals reported (Lek et al., 2016). We interpret c.462delA as a pathogenic variant
Integrated Genetics/Laboratory Corporation of America 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.
OMIM RCV000133549 SCV000057114 pathogenic Mitochondrial complex I deficiency, nuclear type 1 2014-07-01 no assertion criteria provided literature only

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