Submissions for variant NM_020975.6(RET):c.341G>A (p.Arg114His)

gnomAD frequency: 0.00029  dbSNP: rs76397662

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163885	SCV000214475	benign	Hereditary cancer-predisposing syndrome	2015-11-09	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198261	SCV000252850	benign	Multiple endocrine neoplasia, type 2	2024-01-30	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490359	SCV000267473	benign	Hirschsprung disease, susceptibility to, 1	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000121988	SCV000521034	benign	not specified	2017-01-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755684	SCV000883097	benign	Multiple endocrine neoplasia type 2B	2018-11-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001106778	SCV001263874	likely benign	Renal hypodysplasia/aplasia 1	2017-04-28	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.
Illumina Laboratory Services, Illumina	RCV001106779	SCV001263875	benign	Multiple endocrine neoplasia	2017-04-28	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	RCV001107412	SCV001264555	benign	Pheochromocytoma	2017-04-28	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.
CeGaT Center for Human Genetics Tuebingen	RCV003389668	SCV001500426	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	RET: BP4, BS1
Sema4, Sema4	RCV000163885	SCV002527911	benign	Hereditary cancer-predisposing syndrome	2020-04-28	criteria provided, single submitter	curation
OMIM	RCV000014974	SCV000035230	uncertain significance	Congenital central hypoventilation	2002-04-01	no assertion criteria provided	literature only
ITMI	RCV000121988	SCV000086199	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV004739309	SCV005349601	uncertain significance	RET-related disorder	2024-04-05	no assertion criteria provided	clinical testing	The RET c.341G>A variant is predicted to result in the amino acid substitution p.Arg114His. This variant has been described as a recurrent variant in individuals with Hirschprung disease and Chinese ancestry, although it has also been found in unaffected parents (Garcia-Barceló et al. 2004. PubMed ID: 14633923; Cornes et al. 2010. PubMed ID: 20532249). This variant has also been described in presumably healthy controls and is present in population databases in up to 1.0% individuals, with East Asian descent being the most prevalent (Bodian et al. 2014. PubMed ID: 24728327; Olfson et al. 2015. PubMed ID: 26332594; http://gnomad.broadinstitute.org/variant/10-43597793-G-A). This variant change resides within the Tyrosine-protein kinase, Ret receptor domain. In vitro functional characterization of this variant suggests that it does not result in loss of function, as would be expected for a pathogenic variant in Hirschsprung disease (Kjaer et al. 2010. PubMed ID: 20473317). These observations suggest that the c.314A>G (p.Arg114His) variant is possibly benign or a risk factor for Hirschsprung disease. Although we suspect that this variant may be benign, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic information.