rs267607164
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_006086.4(TUBB3):c.1249G>A(p.Asp417Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D417H) has been classified as Pathogenic.
Frequency
Consequence
NM_006086.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB3 | NM_006086.4 | c.1249G>A | p.Asp417Asn | missense_variant | 4/4 | ENST00000315491.12 | |
TUBB3 | NM_001197181.2 | c.1033G>A | p.Asp345Asn | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB3 | ENST00000315491.12 | c.1249G>A | p.Asp417Asn | missense_variant | 4/4 | 1 | NM_006086.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 08, 2010 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2021 | This sequence change replaces aspartic acid with asparagine at codon 417 of the TUBB3 protein (p.Asp417Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with axonal peripheral neuropathy and/or congenital fibrosis of the extraocular muscles (PMID: 24257358, 25482575). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6966). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. - |
TUBB3-related tubulinopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Mar 12, 2024 | The heterozygous p.Asp417Asn variant in TUBB3 was identified by our study in one individual with congenital fibrosis of the extraocular muscles. This variant is assumed de novo in the individual, but maternity and paternity have not been confirmed. The p.Asp417Asn variant in TUBB3 has been previously reported in at least 7 unrelated individuals with congenital fibrosis of extraocular muscles 3A with or without extraocular involvement (PMID: 24257358, PMID: 25482575, PMID: 20074521, PMID: 34418069) and segregated with disease in 17 affected relatives from 4 families (PMID: 24257358, PMID: 25482575, PMID: 20074521). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in one individual with confirmed paternity and maternity (PMID: 20074521). This variant has also been reported in ClinVar (Variation ID: 6966) and has been interpreted as pathogenic by Invitae and OMIM. This variant was absent from large population studies. The number of missense variants reported in TUBB3 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. The p.Asp417 variant is located in a region of TUBB3 that is essential to interactions with other motor proteins, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 20074521). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asp417His, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 20301522, Variation ID: 6965). In vitro functional studies provide some evidence that the p.Asp417Asn variant may impact protein function (PMID:31226147, PMID: 29382549). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital fibrosis of extraocular muscles 3A with or without extraocular involvement. ACMG/AMP Criteria applied: PS2_Supporting, PS3_Supporting, PS4, PM1_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1_Strong (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at