Submissions for variant NM_024996.7(GFM1):c.127A>G (p.Asn43Asp)

gnomAD frequency: 0.00900  dbSNP: rs35942089

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000125223	SCV000168664	benign	not specified	2014-01-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000361226	SCV000441848	benign	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000125223	SCV000539236	likely benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, gene associated with combined oxidative phosphorylation deficiency
Labcorp Genetics (formerly Invitae), Labcorp	RCV000964843	SCV001112086	benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV000361226	SCV001736837	benign	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2021-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000964843	SCV002544842	benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	GFM1: BP4, BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV000361226	SCV002802905	likely benign	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2021-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000125223	SCV003801198	benign	not specified	2023-01-31	criteria provided, single submitter	clinical testing	Variant summary: GFM1 c.127A>G (p.Asn43Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0096 in 251432 control chromosomes, predominantly at a frequency of 0.014 within the Non-Finnish European subpopulation in the gnomAD database, including 14 homozygotes, suggesting a benign role of the gene. c.127A>G has been reported in the literature in individuals affected with unspecified mitochondrial disorder without evidence for causality (Wang_2011). This report does not provide unequivocal conclusions about association of the variant with Hepatoencephalopathy Due To Combined Oxidative Phosphorylation Defect Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=5), likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000964843	SCV005260943	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000361226	SCV002081584	benign	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2019-11-12	no assertion criteria provided	clinical testing