Submissions for variant NM_020442.6(VARS2):c.1834_1835del (p.Leu612fs)

gnomAD frequency: 0.00002  dbSNP: rs777028011

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000987662	SCV001137067	likely pathogenic	Combined oxidative phosphorylation defect type 20	2019-05-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000987662	SCV002769056	pathogenic	Combined oxidative phosphorylation defect type 20	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 20 (MIM#615917). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an individual. This variant has been reported as likely pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0702 - Other NMD predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar, PMID: 29314548, 24827421, 31623496). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000987662	SCV003923147	likely pathogenic	Combined oxidative phosphorylation defect type 20	2023-03-03	criteria provided, single submitter	clinical testing	Variant summary: VARS2 c.1834_1835delCT (p.Leu612ValfsX100) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position are classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4.1e-06 in 246348 control chromosomes. To our knowledge, no occurrence of c.1834_1835delCT in individuals affected with Combined Oxidative Phosphorylation Defect Type 20 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV004588446	SCV005079661	likely pathogenic	not provided	2024-03-07	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge