Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000414504 | SCV000491133 | likely pathogenic | not provided | 2016-08-25 | criteria provided, single submitter | clinical testing | The c.1162+4A>C variant in the NDUFV1 gene has been reported previously opposite of a frameshift variant in the second NDUFV1 allele, in a patient with infantile onset intractable seizures, lactic acidemia, cerebellar ataxia, psychomotor regression, strabismus, ptosis and complex 1 deficiency confirmed in muscle and liver (Benit et al., 2001). This variant reduces the quality of the splice donor site in intron 8, and is expected to cause abnormal gene splicing. The c.1162+4A>C variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.1162+4A>C as a likely pathogenic variant. |
Fulgent Genetics, |
RCV000763270 | SCV000893914 | pathogenic | Mitochondrial complex I deficiency, nuclear type 1 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001778956 | SCV002015198 | likely pathogenic | Leigh syndrome | 2021-10-06 | criteria provided, single submitter | clinical testing | Variant summary: NDUFV1 c.1162+4A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site, while two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, and demonstrated exon 8 skipping (Nafisinia_2016). The variant allele was found at a frequency of 6e-05 in 251302 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFV1 causing Leigh Syndrome (0.0013), allowing no conclusion about variant significance. c.1162+4A>C has been reported in the literature in multiple compound heterozygous individuals affected with Leigh Syndrome (Benit_2001, Leman_2015, Nafisinia_2016, Zhang_2021). These data indicate that the variant may be associated with disease. Some of these publications reported experimental evidence evaluating an impact on protein function, and demonstrated decreased complex I protein level, defective assembly and decreased activity in patient derived cells (e.g. Leman_2015, Nafisinia_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic / likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Invitae | RCV000414504 | SCV002111967 | pathogenic | not provided | 2023-12-20 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 8 of the NDUFV1 gene. It does not directly change the encoded amino acid sequence of the NDUFV1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs199683937, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of mitochondrial complex I deficiency (PMID: 11349233, 26024641, 27344648, 34134969; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1192+4A>C . ClinVar contains an entry for this variant (Variation ID: 372716). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
OMIM | RCV000015104 | SCV000035361 | pathogenic | Mitochondrial complex 1 deficiency, nuclear type 4 | 2001-06-01 | no assertion criteria provided | literature only |