rs80338934

Positions:

• chr5-149010272-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024577.4(SH3TC2):​c.3325C>T​(p.Arg1109Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SH3TC2 NM_024577.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.02156
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1 O:1
• Conservation: PhyloP100: 1.47

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-149010272-G-A is Pathogenic according to our data. Variant chr5-149010272-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149010272-G-A is described in Lovd as [Pathogenic]. Variant chr5-149010272-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.3325C>T	p.Arg1109Ter	stop_gained, splice_region_variant	14/17	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.3325C>T	p.Arg1109Ter	stop_gained, splice_region_variant	14/17	1	NM_024577.4	ENSP00000423660	P2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251406 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.0000426 AC XY: 31 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000491 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 4C Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.3325C>T(p.Arg1109Ter) variant has been reported in more than 10 individuals with Charcot-Marie-Tooth disease type 4C and segregated with disease in 16 affected family members from families (Yuan 2018). It has been shown to be a founder mutation in the Spanish Gypsy population (Cl aramunt 2007). This variant has been reported to the ClinVar database as Pathogenic. The variant has been reported in gnomAD database (0.004%) and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. The nucleotide change in SH3TC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons the variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 16326826). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jun 23, 2023	The homozygous pathogenic variant c.3325C>T (p.Arg1109*) has been identified in a proband with phenotypic features of motor delay, frequent falls, difficulty in climbing stairs, asymmetry of face, proximal muscle weakness of lower limbs, positive Romberg’s sign. This variant is identified in exon 14 of SH3TC2 gene. Loss of function is a reported mechanism in SH3TC2 with 104 null pathogenic variants. This variant is predicted to cause NMD. Hence, the ACMG criteria of PVS1_very strong is met. The variant is present in 0.0042% in gnomAD (aggregated) database (PM2_moderate). It has been previously reported (PP5_supporting) PMID 16806930. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 22, 2022	PVS1, PM2, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 10, 2018	The p.Arg1109X variant in SH3TC2 has been reported in more than 10 individuals w ith Charcot-Marie-Tooth disease type 4C and segregated with disease in 16 affect ed family members from families (Gooding 2005, Colomer 2006, Claramunt 2007, Sev illa 2013, Piscosquito 2016, Lupo 2016, Khadilkar 2017, Yuan 2018). It has been shown to be a founder mutation in the Spanish Gypsy population (Gooding 2005, Cl aramunt 2007). It has also been identified in 0.02% (7/30778) of South Asian chr omosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant lea ds to a premature termination codon at position 1109, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Charcot-Marie-Tooth disease ty pe 4C based on case observations, segregation studies, and predicted impact on p rotein. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 04, 2022	PP1, PM2, PM3, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29321516, 30373780, 30653784, 17470135, 22978647, 25525159, 20301514, 16326826, 31634715, 31127727, 31589614, 32376792) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Charcot-Marie-Tooth disease Pathogenic:2 Uncertain:1

Likely pathogenic, no assertion criteria provided	provider interpretation	Inherited Neuropathy Consortium	-	- -
Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -

Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 29, 2021

- -

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2023

This sequence change creates a premature translational stop signal (p.Arg1109*) in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). This variant is present in population databases (rs80338934, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Charcot-Marie-Tooth disease, type 4C (CMT4C) (PMID: 16326826, 17470135, 22978647, 26752306, 27231023). It is commonly reported in individuals of Spanish ancestry (PMID: 16326826, 17470135). ClinVar contains an entry for this variant (Variation ID: 2483). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Benign	0.97
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.94
GERP RS		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.022
dbscSNV1_RF	Benign	0.33
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: rs80338934; hg19: chr5-148389835; COSMIC: COSV60463545; COSMIC: COSV60463545;