NM_024577.4(SH3TC2):c.1972C>T (p.Arg658Cys) AND Charcot-Marie-Tooth disease type 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000654080.8

Allele description [Variation Report for NM_024577.4(SH3TC2):c.1972C>T (p.Arg658Cys)]

NM_024577.4(SH3TC2):c.1972C>T (p.Arg658Cys)

Gene:

SH3TC2:SH3 domain and tetratricopeptide repeats 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q32

Genomic location:

Preferred name:

NM_024577.4(SH3TC2):c.1972C>T (p.Arg658Cys)

HGVS:

NC_000005.10:g.149027760G>A
NG_007947.2:g.40415C>T
NM_024577.4:c.1972C>TMANE SELECT
NP_078853.2:p.Arg658Cys
NP_078853.2:p.Arg658Cys
LRG_269t1:c.1972C>T
LRG_269:g.40415C>T
LRG_269p1:p.Arg658Cys
NC_000005.9:g.148407323G>A
NM_024577.3:c.1972C>T
NM_024577.4:c.1972C>T
Q8TF17:p.Arg658Cys

Protein change:

R658C

Links:

UniProtKB: Q8TF17#VAR_018270; dbSNP: rs80338926

NCBI 1000 Genomes Browser:

rs80338926

Molecular consequence:

NM_024577.4:c.1972C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease type 4
Synonyms:: Charcot-Marie-Tooth, Type 4
Identifiers:: MONDO: MONDO:0018995; MedGen: C4082197

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cyclic nucleotide-binding domain-containing protein [Paraburkholderia acidiphila...
cyclic nucleotide-binding domain-containing protein [Paraburkholderia acidiphila]
gi|1787165038|gnl|PRJNA534068|FAZ97 0|gb|QGZ59056.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000775970	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14574644, 16924012, 21291453, 22462672, 19744956, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000775970

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 23, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.

Senderek J, Bergmann C, Stendel C, Kirfel J, Verpoorten N, De Jonghe P, Timmerman V, Chrast R, Verheijen MH, Lemke G, Battaloglu E, Parman Y, Erdem S, Tan E, Topaloglu H, Hahn A, Müller-Felber W, Rizzuto N, Fabrizi GM, Stuhrmann M, Rudnik-Schöneborn S, Züchner S, et al.

Am J Hum Genet. 2003 Nov;73(5):1106-19. Epub 2003 Oct 21.

PubMed [citation]

PMID:: 14574644
PMCID:: PMC1180490

Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations.

Azzedine H, Ravisé N, Verny C, Gabrëels-Festen A, Lammens M, Grid D, Vallat JM, Durosier G, Senderek J, Nouioua S, Hamadouche T, Bouhouche A, Guilbot A, Stendel C, Ruberg M, Brice A, Birouk N, Dubourg O, Tazir M, LeGuern E.

Neurology. 2006 Aug 22;67(4):602-6.

PubMed [citation]

PMID:: 16924012

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000775970.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SH3TC2 protein function. Experimental studies have shown that this missense change affects SH3TC2 function (PMID: 19744956). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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