Submissions for variant NM_002491.3(NDUFB3):c.19C>T (p.His7Tyr)

gnomAD frequency: 0.00065  dbSNP: rs144513268

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195930	SCV000251843	uncertain significance	not provided	2019-01-21	criteria provided, single submitter	clinical testing	p.His7Tyr (CAT>TAT): c.19 C>T in exon 2 of the NDUFB3 gene (NM_002491.2) The H7Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H7Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties as Histidine are conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195930	SCV001040612	likely benign	not provided	2025-01-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000195930	SCV001553617	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NDUFB3 p.His7Tyr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs144513268), ClinVar (classified as a VUS by GeneDx) and LOVD 3.0. The variant was identified in control databases in 256 of 281208 chromosomes (2 homozygous) at a frequency of 0.00091 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: Other in 12 of 7168 chromosomes (freq: 0.001674), South Asian in 45 of 30172 chromosomes (freq: 0.001491), European (Finnish) in 36 of 25096 chromosomes (freq: 0.001434), European (non-Finnish) in 160 of 128586 chromosomes (freq: 0.001244), Ashkenazi Jewish in 2 of 10364 chromosomes (freq: 0.000193) and Latino in 1 of 35004 chromosomes (freq: 0.000029), while the variant was not observed in the African and East Asian populations. The p.His7 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.