NM_020975.6:c.566G>T

Variant names:

• chr10-43102570-G-T
• rs753707182
• NM_020975.6:c.566G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020975.6(RET):​c.566G>T​(p.Arg189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.29
• Publications: 8 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29502845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.566G>T	p.Arg189Leu	missense_variant	Exon 3 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.566G>T	p.Arg189Leu	missense_variant	Exon 3 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251280 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Uncertain:1

Jul 19, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with leucine at codon 189 of the RET protein (p.Arg189Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RET-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R189L variant (also known as c.566G>T), located in coding exon 3 of the RET gene, results from a G to T substitution at nucleotide position 566. The arginine at codon 189 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	M;.;M
PhyloP100		1.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Benign	0.14
Sift	Benign	0.081	T;.;T
Sift4G	Benign	0.14	T;D;T
Polyphen		0.93	P;.;P
Vest4		0.39
MutPred		0.41		Loss of disorder (P = 0.0646);Loss of disorder (P = 0.0646);Loss of disorder (P = 0.0646);
MVP		0.67
MPC		1.5
ClinPred		0.87	D
GERP RS		2.9
Varity_R		0.14
gMVP		0.73
Mutation Taster		=84/16	polymorphism

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: rs753707182; hg19: chr10-43598018;