rs200983556
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_130837.3(OPA1):c.344C>T(p.Ala115Val) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,612,582 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_130837.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152120Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000221 AC: 55AN: 248414Hom.: 0 AF XY: 0.000252 AC XY: 34AN XY: 134688
GnomAD4 exome AF: 0.000183 AC: 267AN: 1460344Hom.: 0 Cov.: 32 AF XY: 0.000191 AC XY: 139AN XY: 726646
GnomAD4 genome AF: 0.000118 AC: 18AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74428
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
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In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in unrelated patients with optic atrophy and ataxia, and in a patient with retinitis pigmentosa, in published literature, but familial segregation information was not provided (PMID: 20157015, 25564500, 28981474); This variant is associated with the following publications: (PMID: 28981474, 25564500, 33841295, 39072298, 20157015) -
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not specified Uncertain:2
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Variant summary: OPA1 c.344C>T (p.Ala115Val) results in a non-conservative amino acid change located in the Basic domain (Charif_2021) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 248414 control chromosomes. This frequency does not allow conclusions about variant significance although at-least one study reporting a VUS classification for this variant has commented on this frequency as being "probably too common despite literature" (example, Comander_2017). c.344C>T has been reported in the literature among cohorts of individuals with features of OPA1-related disorders ranging from optic atrophy, deafness, pericentral retinitis pigmentosa (RP)/inherited optic neuropathy, ataxia, and unspecified neuropathy (example, Santarelli_2015, Yu-Wai-Man_2010, Gaier_2017, Comander_2017, Charif_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Uncertain:1
This variant was identified in a 10 year old male with autism spectrum disorder, intellectual disability, and dietary selectivity. This variant was maternally inherited and there is no family history of optic atrophy or neurological or mitochondrial dysfunction. Clinical correlation with OPA-related disorders was thought to be poor. The variant is present in the gnomAD South Asian population at 0.068%. Computational prediction models are inconsistent. It has been reported previously in a 5 year old female with optic atrophy, deafness, ataxia, and mild myopathic changes though parental testing was not reported (Santarelli, 2015), and in a 12 year old female with optic atrophy, atixia, and neuropathy (Yu-Wai-Man, 2010). A second, paternally-inherited in-frame deletion, classified as a variant of uncertain signficance, was also identified in the OPA1 gene. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at