Submissions for variant NM_181458.4(PAX3):c.873dup (p.Gly292fs)

dbSNP: rs1553572976

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606448	SCV000731453	pathogenic	Rare genetic deafness	2017-01-31	criteria provided, single submitter	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.
Institute of Human Genetics, University Hospital Muenster	RCV002287430	SCV002577955	pathogenic	See cases	2022-01-20	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP3,PP5
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531677	SCV003524996	pathogenic	not provided	2024-11-23	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056329	SCV005726317	pathogenic	Waardenburg syndrome type 1	2024-11-14	criteria provided, single submitter	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.
GeneDx	RCV002531677	SCV006080238	likely pathogenic	not provided	2024-11-15	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 188 amino acid(s) are replaced with 117 different amino acid(s), and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20127975)