rs377767440

Variant names:

• chr10-43114598-G-TTCT
• rs377767440
• NM_020975.6:c.1998delGinsTTCT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4_Supporting PM5 PP5_Very_Strong

The NM_020975.6(RET):​c.1998delGinsTTCT​(p.Lys666delinsAsnSer) variant causes a missense, conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K666M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 missense, conservative_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.53

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_020975.6. Strenght limited to Supporting due to length of the change: 1aa.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43114597-A-T is described in Lovd as [Pathogenic].
• PP5: Variant 10-43114598-G-TTCT is Pathogenic according to our data. Variant chr10-43114598-G-TTCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1897685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.1998delGinsTTCT	p.Lys666delinsAsnSer	missense_variant, conservative_inframe_insertion	Exon 11 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1998delGinsTTCT	p.Lys666delinsAsnSer	missense_variant, conservative_inframe_insertion	Exon 11 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2A Pathogenic:1

Jan 05, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16954442]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16954442, 15844786, 17639053, 27673361, 29408964, 20103606]. -

Multiple endocrine neoplasia, type 2 Pathogenic:1

May 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial medullary thyroid carcinoma (PMID: 1694442, 15844786, 16954442; Invitae). It has also been observed to segregate with disease in related individuals. This variant, c.1998delinsTTCT , is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the RET protein (p.Lys666delinsAsnSer). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects RET function (PMID: 16954442). This variant is also known as c.2646delGinsTTCT or Lys666Asn, ins Ser. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs377767440; hg19: chr10-43610046;