Submissions for variant NM_152416.4(NDUFAF6):c.298-768T>C

gnomAD frequency: 0.00004  dbSNP: rs575462405

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001875774	SCV002240899	pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the NDUFAF6 gene. It does not directly change the encoded amino acid sequence of the NDUFAF6 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fanconi syndrome (PMID: 27466185). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 917900). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 27466185). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001875774	SCV002756709	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	Observed in the apparent homozygous state in affected individuals from multiple Acadian families with a variant of Fanconi syndrome (Hartmannova et al., 2016); Published functional studies demonstrate a damaging effect: aberrant splicing, loss of expression in mitochondria, and reduced activity of complex I (Hartmannova H et al., 2016); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 34426522, 27466185)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001175176	SCV005087021	uncertain significance	Fanconi renotubular syndrome 5	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. 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 17 (MIM#618239) and there is limited evidence for an association with Fanconi renotubular syndrome 5 (MIM#618913). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR studies support aberrant splicing particularly when this variant is on the same haplotype as the c.298-731A>G polymorphism (PMID: 27466185). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3 - 7 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. PMID: 27466185 report this variant as homozygous in ten affected individuals from seven families in a founder ethnic sub-population (Acadian, Eastern Canada). Affected individuals had renal Fanconi syndrome and pulmonary fibrosis with no other features associated with mitochondrial complex I deficiency, nuclear type 17 (MIM#618239). This variant has also been reported in ClinVar as a VUS (GeneDx) and pathogenic (Invitae) and was identified as a single heterozygous variant in individuals with diverse, unrelated phenotypes. (SP) 0906 - Segregation evidence for this variant is inconclusive. PMID: 27466185 report this variant as homozygous in ten affected individuals; however, this variant was also noted as homozygous in one unaffected individual. Parental testing results were not provided for most affected individuals. There is also no information available regarding the prevalence of this haplotype in the Acadian community. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. NDFUFAF6 mitochondrial isoform (V_1) was shown to be depleted in affected skin fibroblasts and lung tissue with reduction in mitochondrial complex I subunuits (PMID: 27466185). (SP) 1205 - This variant has been shown to be maternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV001175176	SCV001338775	pathogenic	Fanconi renotubular syndrome 5	2020-06-16	no assertion criteria provided	literature only