Submissions for variant NM_020975.6(RET):c.3185A>G (p.Tyr1062Cys)

gnomAD frequency: 0.00003  dbSNP: rs587778659

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412388	SCV000489763	uncertain significance	Multiple endocrine neoplasia type 2B	2015-12-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000409698	SCV000489764	uncertain significance	Multiple endocrine neoplasia type 2A	2015-12-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532140	SCV000658474	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1062 of the RET protein (p.Tyr1062Cys). This variant is present in population databases (rs587778659, gnomAD 0.005%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 15834508, 21995290, 22174939). ClinVar contains an entry for this variant (Variation ID: 135181). 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. Experimental studies have shown that this missense change affects RET function (PMID: 26395553). 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.
GeneDx	RCV001577914	SCV001805406	uncertain significance	not provided	2024-09-13	criteria provided, single submitter	clinical testing	Identified in individuals with Hirschsprung disease, most of whom were found to inherit the variant from an unaffected parent (PMID: 15834508, 17108762, 21475823, 22174939, 21995290); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate decreased RET and ERK phosphorylation (PMID: 26395553); This variant is associated with the following publications: (PMID: 24728327, 21475823, 17108762, 15834508, 21995290, 22174939, 24336963, 14633923, 26206375, 11061555, 31666091, 26395553)
Ambry Genetics	RCV002321601	SCV002608033	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-27	criteria provided, single submitter	clinical testing	The p.Y1062C pathogenic mutation (also known as c.3185A>G), located in coding exon 19 of the RET gene, results from an A to G substitution at nucleotide position 3185. The tyrosine at codon 1062 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in multiple individuals from unique cohorts of Hirschsprung disease patients (Wu TT et al. J Hum Genet, 2005 Apr;50:168-174; Ruiz-Ferrer M et al. Genet Med, 2006 Nov;8:704-10; Núñez-Torres R et al. BMC Med Genet, 2011 Oct;12:138; So MT et al. PLoS One, 2011 Dec;6:e28986; Jiang Q et al. Orphanet J Rare Dis, 2019 10;14:237). Further, functional analysis using western blotting showed that this alteration resulted in lower activation (phosphorylation levels) of RET and reduced ERK activation (Widowati T et al. Eur J Hum Genet, 2016 06;24:823-9). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unknown.
Baylor Genetics	RCV003460860	SCV004206724	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001577914	SCV004243367	likely pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
ITMI	RCV000121983	SCV000086194	not provided	not specified	2013-09-19	no assertion provided	reference population