Submissions for variant NM_152416.4(NDUFAF6):c.532G>C (p.Ala178Pro)

gnomAD frequency: 0.00004  dbSNP: rs201088736

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001591048	SCV001823735	uncertain significance	not provided	2021-02-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29531337, 27623250)
Neuberg Centre For Genomic Medicine, NCGM	RCV000412564	SCV002072924	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 17		criteria provided, single submitter	clinical testing	The missense variant p.A178P in NDUFAF6 (NM_152416.4) has been reported in an affected patient in compound heterozygous state with a deep intronic variant (Bianciardi L et al).Functional studies revealed a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.A178P missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.532 in NDUFAF6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252113	SCV002523233	uncertain significance	See cases	2019-03-12	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PP3, PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000412564	SCV002767985	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 17	2021-05-06	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 17 (MIM#618239). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SQS_PSY domain (PDB, DECIPHER, NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. Three unrelated probands with Leigh syndrome have been reported to be compound heterozygotes with this variant (PMID: 29531337). (SP) 0903 - This variant has insufficient evidence for segregation with disease. A single family with two affected siblings has been reported (PMID: 29531337). (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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001591048	SCV003491810	pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NDUFAF6 protein function. ClinVar contains an entry for this variant (Variation ID: 372254). This missense change has been observed in individual(s) with clinical features of complex 1 deficiency and/or complex 1 deficiency (PMID: 29531337). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs201088736, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 178 of the NDUFAF6 protein (p.Ala178Pro).
Ambry Genetics	RCV002523900	SCV003757070	uncertain significance	Inborn genetic diseases	2022-11-14	criteria provided, single submitter	clinical testing	The c.532G>C (p.A178P) alteration is located in exon 5 (coding exon 5) of the NDUFAF6 gene. This alteration results from a G to C substitution at nucleotide position 532, causing the alanine (A) at amino acid position 178 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412564	SCV005040518	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 17	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: C8orf38 c.532G>C (p.Ala178Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 280728 control chromosomes. c.532G>C has been reported in the literature in trans along with a pathogenic intronic variant in multiple individuals affected with Leigh syndrome (example, Bianciardi_2016, Catania_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly reduced normal complex I activity in patients fibroblasts, which was rescued by normal C8ORF38 (Bianciardi_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27623250, 29531337). ClinVar contains an entry for this variant (Variation ID: 372254). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000412564	SCV000490329	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 17	2020-06-23	no assertion criteria provided	literature only