Submissions for variant NM_007103.4(NDUFV1):c.904A>G (p.Lys302Glu)

dbSNP: rs573896386

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000392931	SCV000373630	uncertain significance	Mitochondrial complex I deficiency, nuclear 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000297655	SCV000373631	uncertain significance	Leigh syndrome	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469124	SCV002766342	uncertain significance	not specified	2022-11-29	criteria provided, single submitter	clinical testing	Variant summary: NDUFV1 c.904A>G (p.Lys302Glu) results in a conservative amino acid change located in the Soluble ligand binding domain (IPR019554) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251344 control chromosomes. This frequency is not significantly higher than estimacted for a pathogenic variant in NDUFV1 causing Leigh Syndrome (6.4e-05 vs 0.0013), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.904A>G in individuals affected with Leigh Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV003243064	SCV003978492	uncertain significance	Inborn genetic diseases	2023-05-23	criteria provided, single submitter	clinical testing	The c.904A>G (p.K302E) alteration is located in exon 6 (coding exon 6) of the NDUFV1 gene. This alteration results from a A to G substitution at nucleotide position 904, causing the lysine (K) at amino acid position 302 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.