VCV002477231.5 - ClinVar

NM_001321075.3(DLG4):c.1598A>G (p.Tyr533Cys)

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001321075.3(DLG4):c.1598A>G (p.Tyr533Cys)

Variation ID: 2477231 Accession: VCV002477231.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7193578 (GRCh38) [ NCBI UCSC ] 17: 7096897 (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	Apr 15, 2023	Jul 23, 2024	Aug 7, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001321075.3:c.1598A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001308004.1:p.Tyr533Cys	missense
NM_001128827.4:c.1589A>G	NP_001122299.1:p.Tyr530Cys	missense
NM_001321074.1:c.1718A>G	NP_001308003.1:p.Tyr573Cys	missense
NM_001321076.3:c.1418A>G	NP_001308005.1:p.Tyr473Cys	missense
NM_001321077.3:c.1418A>G	NP_001308006.1:p.Tyr473Cys	missense
NM_001365.5:c.1727A>G	NP_001356.1:p.Tyr576Cys	missense
NM_001369566.3:c.1517A>G	NP_001356495.1:p.Tyr506Cys	missense
NR_135527.1:n.2928A>G		non-coding transcript variant
NC_000017.11:g.7193578T>C
NC_000017.10:g.7096897T>C
NG_008391.3:g.31472A>G

... more HGVS ... less HGVS

Protein change

Y473C, Y506C, Y573C, Y576C, Y530C, Y533C

Other names

Canonical SPDI

NC_000017.11:7193577:T:C

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.

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

Links

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.
DLG4		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	162	333

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.
Intellectual developmental disorder 62	not provided (1)	no classification provided	-	RCV003458913.3
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jan 23, 2023	RCV003203685.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 7, 2023	RCV004593236.1

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.
Uncertain significance (Jan 23, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003898247.2 First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024	Comment: The c.1727A>G (p.Y576C) alteration is located in exon 18 (coding exon 18) of the DLG4 gene. This alteration results from a A to G substitution … (more) The c.1727A>G (p.Y576C) alteration is located in exon 18 (coding exon 18) of the DLG4 gene. This alteration results from a A to G substitution at nucleotide position 1727, causing the tyrosine (Y) at amino acid position 576 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Aug 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005079054.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
not provided (-)	no classification provided Method: phenotyping only	Intellectual developmental disorder 62 Affected status: unknown Allele origin: maternal, unknown	GenomeConnect - Brain Gene Registry Accession: SCV004176892.2 First in ClinVar: Dec 24, 2023 Last updated: Mar 30, 2024	Comment: Variant classified as Uncertain significance and reported on 08-07-2023 by GeneDx. This variant was identified in the participant's parent enrolled in GenomeConnect. Phenotypic data from … (more) Variant classified as Uncertain significance and reported on 08-07-2023 by GeneDx. This variant was identified in the participant's parent enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect.Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Observation 1: Clinical Features: Dystonic disorder (present) , Delayed speech and language development (present) , Motor stereotypies (present) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Exome Sequencing Testing laboratory: Ambry Genetics Date variant was reported to submitter: 2023-02-24 Testing laboratory interpretation: Uncertain significance Observation 2: Clinical Features: Family history (present) Indication for testing: Family Testing Age: 40-49 years Sex: female Method: Familial/Targeted Variant Analysis Testing laboratory: GeneDx Date variant was reported to submitter: 2023-08-07 Testing laboratory interpretation: Uncertain significance

Comment:

The c.1727A>G (p.Y576C) alteration is located in exon 18 (coding exon 18) of the DLG4 gene. This alteration results from a A to G substitution at nucleotide position 1727, causing the tyrosine (Y) at amino acid position 576 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Comment:

Variant classified as Uncertain significance and reported on 08-07-2023 by GeneDx. This variant was identified in the participant's parent enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect.Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_001321075.3(DLG4):c.1598A>G (p.Tyr533Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...