Submissions for variant NM_001122659.3(EDNRB):c.1285G>A (p.Gly429Arg)

gnomAD frequency: 0.00020  dbSNP: rs144565124

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220584	SCV000271757	uncertain significance	not specified	2015-08-11	criteria provided, single submitter	clinical testing	The p.Gly519Arg variant in EDNRB has not been previously reported in individuals with hearing loss or Waardenburg syndrome, but has been identified in 6/65674 E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs144565124). Although this variant has been seen in the ge neral population, its frequency is not high enough to rule out a pathogenic role . Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical signi ficance of the Gly519Arg variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000402655	SCV000384802	uncertain significance	Waardenburg syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000310434	SCV000384803	uncertain significance	Hirschsprung Disease, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000220584	SCV001362333	uncertain significance	not specified	2019-01-23	criteria provided, single submitter	clinical testing	Variant summary: EDNRB c.1285G>A (p.Gly429Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 275528 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1285G>A in individuals affected with Waardenburg syndrome type 4A and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853450	SCV002311646	uncertain significance	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 429 of the EDNRB protein (p.Gly429Arg). This variant is present in population databases (rs144565124, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EDNRB-related conditions. ClinVar contains an entry for this variant (Variation ID: 228662). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Fulgent Genetics, Fulgent Genetics	RCV002478768	SCV002788065	uncertain significance	ABCD syndrome; Hirschsprung disease, susceptibility to, 2; Waardenburg syndrome type 4A	2022-03-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517548	SCV003737828	uncertain significance	Inborn genetic diseases	2022-10-26	criteria provided, single submitter	clinical testing	The c.1285G>A (p.G429R) alteration is located in exon 8 (coding exon 7) of the EDNRB gene. This alteration results from a G to A substitution at nucleotide position 1285, causing the glycine (G) at amino acid position 429 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.