ClinVar Miner

Submissions for variant NM_181458.4(PAX3):c.580G>A (p.Glu194Lys)

gnomAD frequency: 0.00016  dbSNP: rs148454691
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000606544 SCV000711525 uncertain significance not specified 2017-07-25 criteria provided, single submitter clinical testing The p.Glu194Lys variant in PAX3 has not been previously reported in individuals with hearing loss or Waardenburg syndrome, but it has been identified in 33/1267 14 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org/; dbSNP rs148454691). Although this variant has been seen i n the general population, its frequency is not high enough to rule out a pathoge nic role. Computational prediction tools and conservation analyses do not provid e strong support for or against an impact to the protein. In summary, the clinic al significance of the p.Glu194Lys variant is uncertain.
Fulgent Genetics, Fulgent Genetics RCV000765614 SCV000896938 uncertain significance Alveolar rhabdomyosarcoma; Waardenburg syndrome type 1; Craniofacial-deafness-hand syndrome; Waardenburg syndrome type 3 2018-10-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001139116 SCV001299227 benign Craniofacial-deafness-hand syndrome 2017-09-26 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina RCV001139117 SCV001299228 likely benign Waardenburg syndrome 2017-09-26 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx RCV001770539 SCV002002057 uncertain significance not provided 2022-03-31 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001770539 SCV003476642 uncertain significance not provided 2022-05-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 194 of the PAX3 protein (p.Glu194Lys). This variant is present in population databases (rs148454691, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PAX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 504786). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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