Submissions for variant NM_015965.7(NDUFA13):c.170G>A (p.Arg57His)

gnomAD frequency: 0.00001  dbSNP: rs752513525

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000735414	SCV005086228	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 28	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex I deficiency, nuclear type 28 (MIM#618249) (PMIDs: 25901006, 32722639). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (15 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (26 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated GRIM-19 family domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been observed as homozygous in two siblings with developmental delay, seizures, hypotonia and optic atrophy. The variant was confirmed to be heterozygous in their unaffected parents and an unaffected sibling (PMID: 25901006). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Western blot experiments in fibroblasts from patients homozygous for this variant showed reduced protein levels for NDUFA13 and other CI subunits. Blue native page experiments in these cells also showed a reduction in the abundance of CI and the CI, CIII, CIV supramolecular complex (PMID: 25901006). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
INSERM U1051, Institut des Neurosciences de Montpellier	RCV000239442	SCV000153676	pathogenic	Mitochondrial complex I deficiency	2014-05-01	no assertion criteria provided	research
OMIM	RCV000735414	SCV000611546	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 28	2024-07-16	no assertion criteria provided	literature only