Submissions for variant NM_001086521.2(NDUFAF8):c.195+271C>T

gnomAD frequency: 0.00063  dbSNP: rs745332456

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000984080	SCV000995083	pathogenic	Mitochondrial disease	2019-10-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001003490	SCV001737627	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 34	2021-05-21	criteria provided, single submitter	clinical testing	Variant summary: C17ORF89 (NDUFAF8) c.195+271C>T is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic intronic 5 donor site. Experimental evidence demonstrated this variant was associated with an mRNA defect leading to loss of the functionally relevant transcript (Alston_2020). The variant allele was found at a frequency of 0.00062 in 150992 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD v3.1.1 database. Due to an unknown prevalence of C17ORF89 associated Mitochondrial Complex 1 Deficiency, this frequency relative to that expected for a pathogenic variant in C17ORF89 is unknown, allowing no conclusion about variant significance. c.195+271C>T has been reported in the literature in two comprehensively genotyped compound heterozygous individuals affected with Mitochondrial Complex 1 Deficiency (Alston_2020). Experimental evidence derived from studies on fibroblasts and muscle cells from one of these individuals indicated a decrease in complex I activity, a reduction in oxidative capacity, decreased levels of fully assembled complex I and a generalized reduction in complex I subunits (Alston_2020). These data indicate that the variant may be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Undiagnosed Diseases Network, NIH	RCV001003490	SCV002523170	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 34	2022-03-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002275160	SCV002563447	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	NDUFAF8: PM3:Strong, PM2, PS3:Supporting
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001003490	SCV002769042	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 34	2022-02-02	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 34 (MIM#618776). (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. Functional analysis of patient fibroblasts shows this variant results in intron retention and the loss of isoform 2. However, the exact protein outcome is unclear as this would be expected to result in a truncated protein (PMID: 31866046). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (93 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable intronic variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been described as likely pathogenic and pathogenic, and observed in two unrelated compound heterozygous individuals with Leigh syndrome and complex I deficiency (ClinVar, PMID: 31866046). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV001003490	SCV003836428	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 34	2022-03-30	criteria provided, single submitter	clinical testing
OMIM	RCV001003490	SCV001161786	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 34	2020-04-07	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004754579	SCV005345606	likely pathogenic	NDUFAF8-related disorder	2024-06-06	no assertion criteria provided	clinical testing	The NDUFAF8 c.199+267C>T variant is predicted to interfere with splicing. This variant, also reported as c.195+271C>T in transcript NM_001086521, has been reported in two unrelated individuals with a clinical diagnosis of Leigh syndrome (subjects 1 and 2, Alston et al. 2019. PubMed ID: 31866046). In vitro studies from subject 1's fibroblast cells demonstrated expression of this variant results in aberrant splicing, a reduction in oxidative capacity, as well as decreased levels of fully assembled complex I in both muscle cells and fibroblasts compared to controls (Figures S3, S4 and 3, Alston et al. 2019. PubMed ID: 31866046). Additionally, a rescue assay demonstrated that this phenotype could be corrected by a reintroduction of wildtype (Figure 3, Alston et al. 2019. PubMed ID: 31866046). This variant is reported in 0.12% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.