Submissions for variant NM_175614.5(NDUFA11):c.138G>A (p.Pro46=)

gnomAD frequency: 0.00029  dbSNP: rs138889960

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000914175	SCV000251770	likely benign	not provided	2021-04-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000382120	SCV000414847	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.
Invitae	RCV000914175	SCV001059339	likely benign	not provided	2023-12-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000914175	SCV002498405	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	NDUFA11: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV003947634	SCV004762303	likely benign	NDUFA11-related condition	2022-07-06	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000914175	SCV001552774	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NDUFA11 p.Pro46Pro variant was not identified in the literature nor was it identified in Cosmic and LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs138889960) as “With Uncertain significance allele” and in ClinVar (conflicting interpretations of pathogenicity: likely benign by GeneDx and uncertain significance by Illumina Clinical Services Laboratory; associated phenotype of Mitochondrial complex I deficiency). The variant was identified in control databases in 137 of 282780 chromosomes (1 homozygous) at a frequency of 0.000484 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 49 of 35432 chromosomes (freq: 0.001383), Other in 9 of 7226 chromosomes (freq: 0.001246), South Asian in 15 of 30616 chromosomes (freq: 0.00049), European (non-Finnish) in 60 of 129174 chromosomes (freq: 0.000465), African in 3 of 24960 chromosomes (freq: 0.00012), East Asian in 1 of 19952 chromosomes (freq: 0.00005), while the variant was not observed in the Ashkenazi Jewish, European (Finnish), populations. The p.Pro46Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, and GeneSplicer) predict a greater than 10% difference in splicing (creation of a 3’ splice site at c.139). However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.