10-43113621-T-C

Position:

• chr10-43113621-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-9.1	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.95		Gain of disorder (P = 0.0469);.;Gain of disorder (P = 0.0469);
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77558292; hg19: chr10-43609069;