rs80338924

chr5-149027983-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_024577.4(SH3TC2):c.1747_1748del(p.Arg583AlafsTer4) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R583R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH3TC2 NM_024577.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 5.26

Genes affected

SH3TC2 (HGNC:29427): (SH3 domain and tetratricopeptide repeats 2) This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule. Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-149027983-CCT-C is Pathogenic according to our data. Variant chr5-149027983-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 2479.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-149027983-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3TC2	NM_024577.4	c.1747_1748del	p.Arg583AlafsTer4	frameshift_variant	11/17	ENST00000515425.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3TC2	ENST00000515425.6	c.1747_1748del	p.Arg583AlafsTer4	frameshift_variant	11/17	1	NM_024577.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4C Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2003	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous p.Arg583AlafsTer4 variant in SH3TC2 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 425358), in two siblings with Charcot-Marie-Tooth disease type 4C. Familial exome analysis revealed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 425358). The p.Arg583AlafsTer4 variant in SH3TC2 has been previously reported in two unrelated individuals with Charcot-Marie-Tooth disease type 4C (PMID: 14574644). These previously reported affected individuals were homozygotes (PMID: 14574644) and the siblings identified by our study were compound heterozygotes who carried a pathogenic variant in trans (ClinVar Variation ID: 425358), which increases the likelihood that the p.Arg583AlafsTer4 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 2479) and has been interpreted as pathogenic by OMIM. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 583 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SH3TC2 gene is an established disease mechanism in autosomal recessive Charcot-Marie-Tooth disease type 4C. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Charcot-Marie-Tooth disease type 4C. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong (Richards 2015). -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338924; hg19: chr5-148407546;