Submissions for variant NM_207034.3(EDN3):c.565dup (p.Thr189fs)

dbSNP: rs11570344

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218370	SCV000270181	benign	not specified	2017-07-20	criteria provided, single submitter	clinical testing	p.Thr189fs in exon 4 of EDN3: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (157/25790) of Finnish chromosom es including 2 homozygotes, and 0.3% (381/126686) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 11570344). The variant has been reported in an individual with congenital centra l hypoventilation syndrome and an individual with Hirschsprung disease; however, the variant did not segregate with disease in an affected sibling while several unaffected family members harbored this variant. In addition, in vitro function al analysis indicated no effect on protein expression and the authors pointed ou t that the variant occurs in a region near the 3' end that is cleaved off in the active form of the protein (Bolk 1996, Sanchez-Mejias 2009). In summary, this variant is benign based on its frequency and lack of evidence to support pathoge nicity.
GeneDx	RCV000899895	SCV000329340	benign	not provided	2019-02-15	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation as the last 50 amino acids are replaced with 9 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 19556619, 8696331, 20127975, 30096381)
Illumina Laboratory Services, Illumina	RCV000392916	SCV000434876	likely benign	Hirschsprung Disease, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000899895	SCV001044185	likely benign	not provided	2024-01-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000990323	SCV001141263	likely benign	Waardenburg syndrome type 4B	2019-05-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917894	SCV004734758	likely benign	EDN3-related condition	2019-07-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV000018125	SCV000038404	uncertain significance	Congenital central hypoventilation	1996-08-01	no assertion criteria provided	literature only
Human Genomics Unit, Institute for molecular medicine Finland (FIMM)	RCV000736046	SCV000845746	likely pathogenic	Aganglionic megacolon		no assertion criteria provided	research