chr10-43113621-T-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_020975.6(RET):c.1825T>C(p.Cys609Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C609F) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
RET
NM_020975.6 missense
NM_020975.6 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 6.49
Genes affected
RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_020975.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-43113622-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 38284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 10-43113621-T-C is Pathogenic according to our data. Variant chr10-43113621-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43113621-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1825T>C | p.Cys609Arg | missense_variant | 10/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1825T>C | p.Cys609Arg | missense_variant | 10/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aganglionic megacolon Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Human Genomics Unit, Institute for molecular medicine Finland (FIMM) | Jan 01, 2013 | - - |
Multiple endocrine neoplasia, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 29, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys609 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9230192, 9681851, 16715139, 19472011, 21986619, 24617864). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 13944). This missense change has been observed in individuals with clinical features of multiple endocrine neoplasia type 2 and/or Hirschsprung disease (PMID: 8807338, 10982477, 20516206, 23278115, 23744765, 30763276). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 609 of the RET protein (p.Cys609Arg). - |
Familial medullary thyroid carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 04, 2000 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2015 | The C609R pathogenic variant has been report previously in association with multiple endocrine neoplasia type 2A (Kambouris et al., 1996; Barbieri et al., 2013). In vitro function studies demonstrated that C609R confers a gain-of-function to the protein resulting in enhanced tyrosine autophosphorylation and the ability to phosphorylate downstream target effectors (Chappuis-Flament et al., 1998). The C609R substitution was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C609R variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (C609S, C609G, C609R, C609F, C609Y, C609W) have been reported in the Human Gene Mutation Database in association with RET-related disorders (Stenson et al., 2014). Therefore, we interpret C609R as a pathogenic variant. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 02, 2019 | The p.C609R pathogenic mutation (also known as c.1825T>C), located in coding exon 10 of the RET gene, results from a T to C substitution at nucleotide position 1825. The cysteine at codon 609 is replaced by arginine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple families meeting criteria for MEN2, many of which also had individuals diagnosed with Hirschprung disease (Barbieri RB et al. Clin. Endocrinol. (Oxf) 2013 Aug;79(2):288-93; Bugalho MJ et al. Surgery 2007 Jan;141(1):90-5; Frank-Raue K et al. Hum. Mutat. 2011 Jan;32(1):51-8; Vertanen VB et al. Endocr. Relat. Cancer 2013 Aug;20(4):595-602; Elisei R et al. J. Clin. Endocrinol. Metab. 2007 Dec;92(12):4725-9). Additionally, two well characterized mutations at this position, p.C609S and p.C609G, have been reported in multiple families with MEN2 (Quayle FJ et al. Surgery 2007 Dec;142(6):800-5; discussion 805.e1; Fitze G et al. Am. J. Med. Genet. A 2004 Sep;129A(3):323-5; Simon SJ et al. J. Pediatr. Surg. 2002 Jun;37(6):897-900). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Gain of disorder (P = 0.0469);.;Gain of disorder (P = 0.0469);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at