Submissions for variant NM_021074.5(NDUFV2):c.669_670insG (p.Ser224fs)

gnomAD frequency: 0.00001  dbSNP: rs772188600

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000754626	SCV002767781	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 7	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with mitochondrial complex I deficiency, nuclear type 7 (MIM#618229). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. While it is hypothesised that transcripts containing this variant were still subjected to nonsense-mediated decay (NMD), data was not shown in the manuscript for independent assessment (PMID: 26008862). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). (SP) 0402 - Variant is located in a gene associated with a severe early-onset recessive condition that is intolerant to bi-allelic loss of function variants (gnomAD, OMIM). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable downstream truncating variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. A pair of siblings with hypertrophic cardiomyopathy and encephalopathy were compound heterozygotes for this variant and a splice site variant (PMID: 26008862). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002533771	SCV003278958	uncertain significance	not provided	2022-07-15	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 617494). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 26008862). This variant is present in population databases (rs772188600, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ser224Valfs*3) in the NDUFV2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the NDUFV2 protein.
GeneDx	RCV002533771	SCV004036679	pathogenic	not provided	2023-03-24	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; Published functional studies demonstrate a damaging effect, including dramatically decreased protein level and absence of transcripts containing this variant, indicative of nonsense mediated decay (Cameron et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26008862)
OMIM	RCV000754626	SCV000882546	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 7	2019-01-25	no assertion criteria provided	literature only