rs863224781
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_024577.4(SH3TC2):c.1585_1587delCGTinsTGG(p.Arg529Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R529Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_024577.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.1585_1587delCGTinsTGG | p.Arg529Trp | missense_variant | ENST00000515425.6 | NP_078853.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild Pathogenic:1
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Charcot-Marie-Tooth disease type 4 Pathogenic:1
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been observed in multiple individuals affected with autosomal recessive Charcot-Marie-Tooth disease (CMT4) (PMID: 30001926). ClinVar contains an entry for this variant (Variation ID: 216738). This sequence change replaces arginine with tryptophan at codon 529 of the SH3TC2 protein (p.Arg529Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at