rs1553572976

Variant names:

• chr2-222221306-C-CG
• rs1553572976
• NM_181458.4:c.873dupC

Variant summary

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

The NM_181458.4(PAX3):​c.873dupC​(p.Gly292ArgfsTer118) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P291P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX3 NM_181458.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -1.58

Genes affected

PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

LOC107985991 (HGNC:):

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 2-222221306-C-CG is Pathogenic according to our data. Variant chr2-222221306-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 517263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.873dupC	p.Gly292ArgfsTer118	frameshift_variant	Exon 6 of 9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.873dupC	p.Gly292ArgfsTer118	frameshift_variant	Exon 6 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

See cases Pathogenic:1

Jan 20, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM2,PP3,PP5 -

Waardenburg syndrome type 1 Pathogenic:1

Nov 14, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAX3 c.873dupC (p.Gly292ArgfsX118) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251192 control chromosomes. c.873dupC has been reported in the literature in individuals affected with Waardenburg Syndrome (example: Pingault_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 20127975). ClinVar contains an entry for this variant (Variation ID: 517263). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly292Argfs*118) in the PAX3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 188 amino acid(s) of the PAX3 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Waardenburg syndrome, type 3 (PMID: 20127975). ClinVar contains an entry for this variant (Variation ID: 517263). This variant disrupts a region of the PAX3 protein in which other variant(s) (p.Gln405Argfs*29) have been determined to be pathogenic (PMID: 9654197; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Jan 31, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly291fs variant in PAX3 has been reported in 1 individual with Waardenbur g syndrome type I (Pingault 2010). It has not been identified in large populati on studies. This variant is predicted to cause a frameshift, which alters the pr otein?s amino acid sequence beginning at position 291 and leads to a premature t ermination codon 118 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Heterozygous loss of function of the PA X3 gene is an established disease mechanism in Waardenburg syndrome. In summary, this variant meets criteria to be classified as pathogenic for Waardenburg synd rome in an autosomal dominant manner based upon its predicted impact to the prot ein, presence in a previously reported affected individual, and extremely low fr equency in the general population. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1553572976; hg19: chr2-223086025;