VCV000167718.25 - ClinVar

NM_005634.3(SOX3):c.157G>C (p.Val53Leu)

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.

(12)

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
Likely pathogenic(1); Benign(3); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005634.3(SOX3):c.157G>C (p.Val53Leu)

Variation ID: 167718 Accession: VCV000167718.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq27.1 X: 140504904 (GRCh38) [ NCBI UCSC ] X: 139587069 (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	Jun 28, 2015	Nov 24, 2024	Jan 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005634.3:c.157G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005625.2:p.Val53Leu	missense
NC_000023.11:g.140504904C>G
NC_000023.10:g.139587069C>G
NG_009387.1:g.5157G>C
NG_051085.1:g.203C>G

... more HGVS ... less HGVS

Protein change

V53L

Other names

Canonical SPDI

NC_000023.11:140504903:C:G

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.

0.00265 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00097

1000 Genomes Project 0.00265

1000 Genomes Project 30x 0.00291

The Genome Aggregation Database (gnomAD) 0.00403

Trans-Omics for Precision Medicine (TOPMed) 0.00524

The Genome Aggregation Database (gnomAD), exomes 0.00744

Exome Aggregation Consortium (ExAC) 0.00934

Links

ClinGen: CA180451 dbSNP: rs200361128 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.
SOX3		No evidence available	Some evidence for dosage pathogenicity	GRCh38 GRCh37	78	288
LOC108281134	-	-	-	GRCh38	-	114

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	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Oct 18, 2023	RCV000153990.21
History of neurodevelopmental disorder	Benign (1)	criteria provided, single submitter	Dec 3, 2012	RCV000720991.9
Abnormal brain morphology	Likely pathogenic (1)	criteria provided, single submitter	-	RCV000454344.9
not provided	Benign (3)	criteria provided, single submitter	Jan 15, 2024	RCV000878811.17
Intellectual disability, X-linked, with panhypopituitarism	Likely benign (1)	criteria provided, single submitter	Jul 17, 2023	RCV004593993.2

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.
Likely benign (Jun 29, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000203615.7 First in ClinVar: Feb 02, 2015 Last updated: Jun 28, 2015	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SOX3 Number of individuals with the variant: 3 Sex: mixed
Likely benign (Mar 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002066086.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Oct 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847355.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Val53Leu variant in SOX3 is classified as benign because it has been identified in 2.1% of African/African American chromosomes, including 1 homozygote, in gnomAD … (more) The p.Val53Leu variant in SOX3 is classified as benign because it has been identified in 2.1% of African/African American chromosomes, including 1 homozygote, in gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is higher than expected for a disease causing variant in SOX3. ACMG/AMP Criteria applied: BA1. (less)
Likely pathogenic (-)	criteria provided, single submitter (Karaca et al. (Neuron 2015)) Method: research	Abnormal brain morphology (X-linked inheritance) Affected status: yes Allele origin: inherited	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000537978.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Publications: PubMed (1) PubMed: 26539891 Geographic origin: Turkey Tissue: Blood
Benign (Dec 03, 2012)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015)) Method: clinical testing	History of neurodevelopmental disorder Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000851875.3 First in ClinVar: Nov 08, 2018 Last updated: Nov 08, 2018	Comment: This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more) This alteration is classified as benign based on a combination of the following: 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) Number of individuals with the variant: 1
Benign (Jan 15, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001021783.4 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked, with panhypopituitarism (X-linked inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086758.2 First in ClinVar: Jul 23, 2024 Last updated: Nov 24, 2024	Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, with more than 300 hemizygous alleles in gnomAD v2 (MIM#300123). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797719.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740656.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001925375.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932787.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001969360.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
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Comment:

The p.Val53Leu variant in SOX3 is classified as benign because it has been identified in 2.1% of African/African American chromosomes, including 1 homozygote, in gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is higher than expected for a disease causing variant in SOX3. ACMG/AMP Criteria applied: BA1.

Comment:

This alteration is classified as benign based on a combination of the following: 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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, with more than 300 hemizygous alleles in gnomAD v2 (MIM#300123). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.	Karaca E	Neuron	2015	PMID: 26539891
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SOX3	-	-	-	-

Text-mined citations for rs200361128 ...

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_005634.3(SOX3):c.157G>C (p.Val53Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200361128 ...