Submissions for variant NM_001002755.4(NFU1):c.676A>G (p.Asn226Asp)

gnomAD frequency: 0.00004  dbSNP: rs377381866

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479200	SCV000565324	likely pathogenic	not provided	2013-10-16	criteria provided, single submitter	clinical testing	A N22D missense change that is likely pathogenic was identified in the NFU1 gene. It has not been published as a pathogenic variant nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative as an uncharged Asparagine residue is replaced by a negatively charged Aspartic Acid residue. This change occurs at a highly conserved position in the NFU1 protein, and multiple in-silico analysis programs predict that N22D is damaging to the NFU1 protein. Therefore, N22D is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001217924	SCV001389784	uncertain significance	Multiple mitochondrial dysfunctions syndrome 1	2019-07-30	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NFU1-related disease. ClinVar contains an entry for this variant (Variation ID: 418385). This variant is present in population databases (rs377381866, ExAC 0.001%). This sequence change replaces asparagine with aspartic acid at codon 226 of the NFU1 protein (p.Asn226Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317233	SCV004020749	uncertain significance	not specified	2023-06-23	criteria provided, single submitter	clinical testing	Variant summary: NFU1 c.676A>G (p.Asn226Asp) results in a conservative amino acid change located in the C-terminal domain (IPR001075) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.676A>G in individuals affected with Multiple Mitochondrial Dysfunctions Syndrome 1 has been reported. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant may have an impact on protein-protein interactions as well as a defect in lipoylation, however, these findings did not allow convincing conclusions about the variant effect (e.g., Jain_2020). The following publication was ascertained in the context of this evaluation (PMID: 32776106). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.