5-149028145-AC-CT

Position:

• chr5-149028145-AC-CT

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Moderate PM1 PM2 PM5 PP3 PP5_Very_Strong

The ENST00000515425.6(SH3TC2):​c.1586_1587delinsAG​(p.Arg529Gln) 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R529H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH3TC2 ENST00000515425.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91

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 17 ACMG points.

• PS1: Transcript ENST00000515425.6 (SH3TC2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a repeat TPR 1 (size 33) in uniprot entity S3TC2_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in ENST00000515425.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-149028147-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 5-149028145-AC-CT is Pathogenic according to our data. Variant chr5-149028145-AC-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.1586_1587delinsAG	p.Arg529Gln	missense_variant	11/17	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.1586_1587delinsAG	p.Arg529Gln	missense_variant	11/17	1	NM_024577.4	ENSP00000423660	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/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 12, 2024	PS3, PM2, PM3_Strong, PM5_Supporting, PP3 -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2021

The c.1586_1587delGTinsAG variant (also known as p.R529Q), located in coding exon 11 of the SH3TC2 gene, results from an in-frame deletion of GT and insertion of AG at nucleotide positions 1586 to 1587. This results in the substitution of the arginine residue for a glutamine residue at codon 529, an amino acid with highly similar properties. This variant has been reported in the literature in the homozygous state as well as in trans with another likely pathogenic alteration in multiple unrelated patients affected with neuropathy (Senderek J et al. Am. J. Hum. Genet., 2003 Nov;73:1106-19; Lupo V et al. Hum Mol Genet, 2009 Dec;18:4603-14; Yger M et al. J Peripher Nerv Syst, 2012 Mar;17:112-22; Iguchi M et al. Muscle Nerve, 2013 Feb;47:283-6). Functional studies showed an abnormal effect on protein function in an in vitro cell based assay and abnormal localization with reduction or absence from the plasma membrane (Lupo V et al. Hum Mol Genet, 2009 Dec;18:4603-14; Gouttenoire EA et al. Glia, 2013 Jul;61:1041-51). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 529 of the SH3TC2 protein (p.Arg529Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 4C (PMID: 14574644, 19744956, 21840889, 23281072, 28555600). ClinVar contains an entry for this variant (Variation ID: 216005). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SH3TC2 function (PMID: 19744956, 23553667). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224454; hg19: chr5-148407708;