10-43114488-T-C

Variant names:

• chr10-43114488-T-C
• rs377767404
• NM_020975.6:c.1888T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1888T>C​(p.Cys630Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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. C630Y) 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:3
• Conservation: PhyloP100: 7.80
• Publications: 39 publications found

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]

RET Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 34 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 chr10-43114489-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 24909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 10-43114488-T-C is Pathogenic according to our data. Variant chr10-43114488-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 24908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.1888T>C	p.Cys630Arg	missense	Exon 11 of 20	NP_066124.1
	RET	NM_001406743.1		c.1888T>C	p.Cys630Arg	missense	Exon 11 of 21	NP_001393672.1
	RET	NM_001406744.1		c.1888T>C	p.Cys630Arg	missense	Exon 11 of 20	NP_001393673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.1888T>C	p.Cys630Arg	missense	Exon 11 of 20	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.1888T>C	p.Cys630Arg	missense	Exon 11 of 19	ENSP00000344798.4
	RET	ENST00000615310.5	TSL:5	c.1492T>C	p.Cys498Arg	missense	Exon 9 of 17	ENSP00000480088.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:2

Nov 01, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RET c.1888T>C (p.Cys630Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246688 control chromosomes. c.1888T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma (example, Machens_2004, Dourisboure_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Chappuis-Flament_1998). The most pronounced variant effect results in the constitutive activation of the RET receptor consistent with the established gain of function mechanism of disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 630 of the RET protein (p.Cys630Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma (MTC) (PMID: 14561794, 15523405, 16053382, 25440022). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24908). 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: 9879991). This variant disrupts the p.Cys630 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9223675, 17527003, 21054478, 26678667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C630R variant (also known as c.1888T>C), located in coding exon 11 of the RET gene, results from a T to C substitution at nucleotide position 1888. The cysteine at codon 630 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been seen in multiple individuals and families diagnosed with medullary thyroid carcinoma (MTC), as well as in an individual with both an MTC and a parathyroid adenoma (Machens A et al. Surgery, 2004 Nov;136:1083-7; Elisei R et al. J. Clin. Endocrinol. Metab., 2007 Dec;92:4725-9; Romei C et al. Eur J Endocrinol, 2010 Aug;163:301-8; Martins-Costa MC et al. Arch Endocrinol Metab, 2018;62:623-635; Damavandi E et al. J Thyroid Res, 2021 Nov;2021:7250870). Additionally, it was shown to segregate with disease in a large kindred of more than 20 family members (Dourisboure RJ et al. Thyroid, 2005 Jul;15:668-71). This alteration was also shown to be an activating mutation which leads to a constitutive stimulation of the RET receptor by functional analysis (Chappuis-Flament S et al. Oncogene, 1998 Dec;17:2851-61). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.91
Sift	Benign	0.031	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Gain of disorder (P = 0.0188)
MVP		0.98
MPC		0.97
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.86
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs377767404; hg19: chr10-43609936;