VCV000188089.60 - ClinVar

NM_024577.4(SH3TC2):c.3686A>T (p.Asp1229Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(3); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024577.4(SH3TC2):c.3686A>T (p.Asp1229Val)

Variation ID: 188089 Accession: VCV000188089.60

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q32 5: 149004892 (GRCh38) [ NCBI UCSC ] 5: 148384455 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 31, 2016	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024577.4:c.3686A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078853.2:p.Asp1229Val	missense
NC_000005.10:g.149004892T>A
NC_000005.9:g.148384455T>A
NG_007947.2:g.63283A>T
LRG_269:g.63283A>T
LRG_269t1:c.3686A>T	LRG_269p1:p.Asp1229Val

... more HGVS ... less HGVS

Protein change

D1229V

Other names

Canonical SPDI

NC_000005.10:149004891:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00200 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00200

1000 Genomes Project 30x 0.00234

Exome Aggregation Consortium (ExAC) 0.00248

The Genome Aggregation Database (gnomAD), exomes 0.00262

The Genome Aggregation Database (gnomAD) 0.00306

Trans-Omics for Precision Medicine (TOPMed) 0.00328

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00331

Links

ClinGen: CA334024 dbSNP: rs146920285 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SH3TC2		-	-	GRCh38 GRCh37	1746	1788

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Mar 10, 2020	RCV000237055.22
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jul 1, 2024	RCV000713265.44
Charcot-Marie-Tooth disease	Likely benign (2)	criteria provided, single submitter	-	RCV000789576.3
Charcot-Marie-Tooth disease type 4C	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 28, 2019	RCV000987610.8
Charcot-Marie-Tooth disease type 4	Likely benign (1)	criteria provided, single submitter	Jan 29, 2024	RCV001082893.8
Susceptibility to mononeuropathy of the median nerve, mild	Uncertain significance (1)	criteria provided, single submitter	Feb 13, 2018	RCV001157181.5
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Jun 22, 2021	RCV002453563.3
SH3TC2-related disorder	Likely benign (1)	no assertion criteria provided	Mar 16, 2020	RCV004535140.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Mar 10, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000843854.2 First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2021	Publications: PubMed (5) PubMed: 21291453‚ 25025039‚ 26392352‚ 26257172‚ 25188385
Uncertain significance (Jan 22, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000339049.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SH3TC2 Number of individuals with the variant: 1 Sex: mixed
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136995.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Feb 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Susceptibility to mononeuropathy of the median nerve, mild Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001318731.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001318730.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 21291453 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001335908.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020
Likely benign (Aug 25, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000292687.9 First in ClinVar: Jul 24, 2016 Last updated: Apr 09, 2018	Comment: This variant is associated with the following publications: (PMID: 21291453, 27884173, 25025039, 27582484, 32376792)
Uncertain significance (Nov 08, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000297314.3 First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022
Likely benign (Feb 22, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001433771.2 First in ClinVar: Sep 27, 2020 Last updated: Jun 10, 2023	Comment: The c.3686A>T; p.Asp1229Val variant (rs146920285) has been reported in the heterozygous state, in the absence of any other detected pathogenic SH3TC2 variants, in two HMSN … (more) The c.3686A>T; p.Asp1229Val variant (rs146920285) has been reported in the heterozygous state, in the absence of any other detected pathogenic SH3TC2 variants, in two HMSN I patients (Lassuthova 2011) and one CMT2 patient; however, the variant did not segregate with disease in the CMT family (Hoyer 2014). This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.4% (identified on 510 out of 126,418 chromosomes), in the Saudi Human Genome Program with a frequency of 2.6% (identified on 102 out of 3,920 chromosomes; Abouelhoda 2016), and is classified as likely benign/uncertain significance in ClinVar (ID: 188089). Based on the available information, the p.Asp1229Val variant is likely to be benign. (less)
Likely benign (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000218575.12 First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024
Likely benign (Jun 22, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002614252.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 21291453‚ 25025039‚ 26257172‚ 26392352 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001154547.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: SH3TC2: BS1, BS2 Number of individuals with the variant: 16
Likely benign (Mar 16, 2020)	no assertion criteria provided Method: clinical testing	SH3TC2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004738370.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Uncertain significance (-)	no assertion criteria provided Method: literature only	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Accession: SCV000928932.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Publications: PubMed (1) PubMed: 21291453
click to load more click to collapse

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The c.3686A>T; p.Asp1229Val variant (rs146920285) has been reported in the heterozygous state, in the absence of any other detected pathogenic SH3TC2 variants, in two HMSN I patients (Lassuthova 2011) and one CMT2 patient; however, the variant did not segregate with disease in the CMT family (Hoyer 2014). This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.4% (identified on 510 out of 126,418 chromosomes), in the Saudi Human Genome Program with a frequency of 2.6% (identified on 102 out of 3,920 chromosomes; Abouelhoda 2016), and is classified as likely benign/uncertain significance in ClinVar (ID: 188089). Based on the available information, the p.Asp1229Val variant is likely to be benign.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability.	Antoniadi T	BMC medical genetics	2015	PMID: 26392352
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.	Gonzaga-Jauregui C	Cell reports	2015	PMID: 26257172
A probabilistic model to predict clinical phenotypic traits from genome sequencing.	Chen YC	PLoS computational biology	2014	PMID: 25188385
Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing.	Høyer H	BioMed research international	2014	PMID: 25025039
High frequency of SH3TC2 mutations in Czech HMSN I patients.	Laššuthová P	Clinical genetics	2011	PMID: 21291453
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SH3TC2	-	-	-	-

Text-mined citations for rs146920285 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_024577.4(SH3TC2):c.3686A>T (p.Asp1229Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146920285 ...