Submissions for variant NM_000514.4(GDNF):c.277C>T (p.Arg93Trp)

gnomAD frequency: 0.00272  dbSNP: rs36119840

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150719	SCV000198137	likely benign	not specified	2014-09-10	criteria provided, single submitter	clinical testing	Arg110Trp in exon 3 of GDNF: This variant has been reported in individuals with various phenotypes including pulmonary presentations (see below). However, it i s not expected to cause disease on its own because it has been identified in 0.3 % (28/8600) of European American chromosomes by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs36119840). Phenotypes of individu als reported to carry this variant include isolated congenital central hypoventi lation syndrome, sporadic pheochromocytoma, Hirschsprung disease, and congenital anomalies of the kidney or urinary tract (reported as Arg93Trp; Angrist 1996, S olomon 1996, Woodward 1997, Amiel 1998, Amiel 2003, Chatterjee 2012). In vitro f unctional studies provide some evidence that the Arg110Trp variant may not impac t protein function (reported as Arg93Trp; Eketjall 2002). In summary, this varia nt is not expected to be disease-causing when seen in isolation, though a modify ing role cannot be fully excluded.
Illumina Laboratory Services, Illumina	RCV000009301	SCV001316513	likely benign	Hirschsprung disease, susceptibility to, 3	2017-04-27	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV000009301	SCV002810037	likely benign	Hirschsprung disease, susceptibility to, 3	2022-04-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512938	SCV003473683	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002512938	SCV004011589	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	GDNF: BS2
Breakthrough Genomics, Breakthrough Genomics	RCV002512938	SCV005259823	likely benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000009301	SCV000029519	risk factor	Hirschsprung disease, susceptibility to, 3	2003-04-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003934815	SCV004755575	likely benign	GDNF-related disorder	2021-04-22	no assertion criteria provided	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).