NM_024577.4:c.1972C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_024577.4(SH3TC2):c.1972C>T(p.Arg658Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_024577.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.1972C>T | p.Arg658Cys | missense_variant | Exon 11 of 17 | ENST00000515425.6 | NP_078853.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251024Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135682
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461604Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17AN XY: 727092
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:5
- -
Functional studies show that R658C alters protein localization (Lupo et al., 2009; Roberts et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21291453, 19744956, 14574644, 31589614, 32376792, 20301514, 22462672, 16924012, 20028792) -
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with CMT in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
PP1, PM3_very_strong, PS3_moderate, PS4 -
- -
Charcot-Marie-Tooth disease type 4C Pathogenic:1Other:1
- -
- -
Charcot-Marie-Tooth disease Pathogenic:1
- -
Inborn genetic diseases Pathogenic:1
The c.1972C>T (p.R658C) alteration is located in exon 11 (coding exon 11) of the SH3TC2 gene. This alteration results from a C to T substitution at nucleotide position 1972, causing the arginine (R) at amino acid position 658 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (7/282422) total alleles studied. The highest observed frequency was 0.004% (1/24950) of African alleles. This alteration was detected in the homozygous state, and in conjunction with another alteration in SH3TC2, in multiple individuals with autosomal recessive SH3TC2-related Charcot-Marie-Tooth disease, type 4 (Thomas, 2022; Taghizadeh, 2020; Yger, 2012; Lussuthova, 2011; Azzedine, 2006; Senderek, 2003). This amino acid position is not well conserved in available vertebrate species. Functional studies show the p.R658C alteration is located around the first TPR domain and affects protein localization (Lupo, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -
Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild Pathogenic:1
- -
Susceptibility to mononeuropathy of the median nerve, mild Pathogenic:1
- -
Charcot-Marie-Tooth disease type 4 Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 658 of the SH3TC2 protein (p.Arg658Cys). This variant is present in population databases (rs80338926, gnomAD 0.004%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type 4C (PMID: 14574644, 16924012, 21291453, 22462672). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21690). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SH3TC2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SH3TC2 function (PMID: 19744956). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at