rs121913660
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_007103.4(NDUFV1):c.1022C>T(p.Ala341Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A341A) has been classified as Likely benign.
Frequency
Consequence
NM_007103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFV1 | NM_007103.4 | c.1022C>T | p.Ala341Val | missense_variant | 7/10 | ENST00000322776.11 | |
NDUFV1 | NM_001166102.2 | c.995C>T | p.Ala332Val | missense_variant | 7/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFV1 | ENST00000322776.11 | c.1022C>T | p.Ala341Val | missense_variant | 7/10 | 1 | NM_007103.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249160Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134690
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461042Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 726690
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 341 of the NDUFV1 protein (p.Ala341Val). This variant is present in population databases (rs121913660, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of mitochondrial complex I deficiency (PMID: 10080174, 15576045). ClinVar contains an entry for this variant (Variation ID: 14058). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NDUFV1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NDUFV1 function (PMID: 14662656, 26345448). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2022 | Published functional studies demonstrate a damaging effect (Grad et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10330338, 23562761, 26345448, 21696386, 29948731, 22310368, 17162199, 18991197, 11579423, 19041632, 14662656, 26004627, 10080174, 34426522, 15576045) - |
Mitochondrial complex 1 deficiency, nuclear type 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Leigh syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2023 | Variant summary: NDUFV1 c.1022C>T (p.Ala341Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249160 control chromosomes (gnomAD). c.1022C>T has been reported in the literature in homozygous individuals affected with isolated complex I deficiency (Schuelke_1999, Bugiani_2004). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function provided conflicting conclusions. Specifically, an animal study utilizing transgenic strains of C. elegans demonstrated the variant to be damaging (Grad_2004), while another study utilizing a yeast model system (Y. lipolytica) concluded the variant behaved normally (Varghese_2015). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Mitochondrial complex I deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Mar 01, 1999 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at