VCV003255589.2 - ClinVar

NM_181458.4(PAX3):c.526del (p.Glu176fs)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_181458.4(PAX3):c.526del (p.Glu176fs)

Variation ID: 3255589 Accession: VCV003255589.2

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2q36.1 2: 222294227 (GRCh38) [ NCBI UCSC ] 2: 223158946 (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	Aug 4, 2024	Aug 25, 2024	Apr 3, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_181458.4:c.526del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_852123.1:p.Glu176fs	frameshift
NM_000438.6:c.526del	NP_000429.2:p.Glu176fs	frameshift
NM_001127366.3:c.523del	NP_001120838.1:p.Glu175fs	frameshift
NM_013942.5:c.526del	NP_039230.1:p.Glu176fs	frameshift
NM_181457.4:c.526del	NP_852122.1:p.Glu176fs	frameshift
NM_181459.4:c.526del	NP_852124.1:p.Glu176fs	frameshift
NM_181460.4:c.526del	NP_852125.1:p.Glu176fs	frameshift
NM_181461.4:c.526del	NP_852126.1:p.Glu176fs	frameshift
NC_000002.12:g.222294228del
NC_000002.11:g.223158947del
NG_011632.1:g.9755del
NG_021186.1:g.1082del
NG_097708.1:g.581del

... more HGVS ... less HGVS

Protein change

E175fs, E176fs

Other names

p.Glu176ArgfsTer17

Canonical SPDI

NC_000002.12:222294226:CC: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.
PAX3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	303	401

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.
Waardenburg syndrome type 1	Likely pathogenic (1)	criteria provided, single submitter	Apr 3, 2020	RCV004596688.2

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 pathogenic (Apr 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Waardenburg syndrome type 1 Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005088822.2 First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024	Comment: This variant is predicted to cause a frameshift and consequent premature termination of the protein (p.Glu176ArgfsTer17) and this will likely result in loss-of-function. Due to … (more) This variant is predicted to cause a frameshift and consequent premature termination of the protein (p.Glu176ArgfsTer17) and this will likely result in loss-of-function. Due to the introduction of a premature stop codon, this aberrant transcript will likely be targeted by the nonsense- mediated mRNA decay (NMD) mechanism [PMID: 15040442]. The variant seems to be a novel variant, as it has not been previously reported in population databases or in the literature. However, several other truncating variants lying downstream of the variant, have been previously reported as pathogenic in the ClinVar database context of Waardenburg syndrome type 1. (less)

Comment:

This variant is predicted to cause a frameshift and consequent premature termination of the protein (p.Glu176ArgfsTer17) and this will likely result in loss-of-function. Due to the introduction of a premature stop codon, this aberrant transcript will likely be targeted by the nonsense- mediated mRNA decay (NMD) mechanism [PMID: 15040442]. The variant seems to be a novel variant, as it has not been previously reported in population databases or in the literature. However, several other truncating variants lying downstream of the variant, have been previously reported as pathogenic in the ClinVar database context of Waardenburg syndrome type 1.

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 Sep 01, 2024

ClinVar Genomic variation as it relates to human health

NM_181458.4(PAX3):c.526del (p.Glu176fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...