NM_020975.6(RET):c.2332G>A (p.Val778Ile) AND Renal hypodysplasia/aplasia 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 28, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000014983.35

Allele description [Variation Report for NM_020975.6(RET):c.2332G>A (p.Val778Ile)]

NM_020975.6(RET):c.2332G>A (p.Val778Ile)

Gene:

RET:ret proto-oncogene [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q11.21

Genomic location:

Preferred name:

NM_020975.6(RET):c.2332G>A (p.Val778Ile)

HGVS:

NC_000010.11:g.43118420G>A
NG_007489.1:g.46352G>A
NM_000323.2:c.2332G>A
NM_001355216.2:c.1570G>A
NM_001406743.1:c.2332G>A
NM_001406744.1:c.2332G>A
NM_001406759.1:c.2332G>A
NM_001406760.1:c.2332G>A
NM_001406761.1:c.2203G>A
NM_001406762.1:c.2203G>A
NM_001406763.1:c.2197G>A
NM_001406764.1:c.2203G>A
NM_001406765.1:c.2197G>A
NM_001406766.1:c.2044G>A
NM_001406767.1:c.2044G>A
NM_001406768.1:c.2068G>A
NM_001406769.1:c.1936G>A
NM_001406770.1:c.2044G>A
NM_001406771.1:c.1894G>A
NM_001406772.1:c.1936G>A
NM_001406773.1:c.1894G>A
NM_001406774.1:c.1807G>A
NM_001406775.1:c.1606G>A
NM_001406776.1:c.1606G>A
NM_001406777.1:c.1606G>A
NM_001406778.1:c.1606G>A
NM_001406779.1:c.1435G>A
NM_001406780.1:c.1435G>A
NM_001406781.1:c.1435G>A
NM_001406782.1:c.1435G>A
NM_001406783.1:c.1306G>A
NM_001406784.1:c.1342G>A
NM_001406785.1:c.1315G>A
NM_001406786.1:c.1306G>A
NM_001406787.1:c.1300G>A
NM_001406788.1:c.1147G>A
NM_001406789.1:c.1147G>A
NM_001406790.1:c.1147G>A
NM_001406791.1:c.1027G>A
NM_001406792.1:c.883G>A
NM_001406793.1:c.883G>A
NM_001406794.1:c.883G>A
NM_020629.2:c.2332G>A
NM_020630.7:c.2332G>A
NM_020975.6:c.2332G>AMANE SELECT
NP_000314.1:p.Val778Ile
NP_001342145.1:p.Val524Ile
NP_001342145.1:p.Val524Ile
NP_001393672.1:p.Val778Ile
NP_001393673.1:p.Val778Ile
NP_001393688.1:p.Val778Ile
NP_001393689.1:p.Val778Ile
NP_001393690.1:p.Val735Ile
NP_001393691.1:p.Val735Ile
NP_001393692.1:p.Val733Ile
NP_001393693.1:p.Val735Ile
NP_001393694.1:p.Val733Ile
NP_001393695.1:p.Val682Ile
NP_001393696.1:p.Val682Ile
NP_001393697.1:p.Val690Ile
NP_001393698.1:p.Val646Ile
NP_001393699.1:p.Val682Ile
NP_001393700.1:p.Val632Ile
NP_001393701.1:p.Val646Ile
NP_001393702.1:p.Val632Ile
NP_001393703.1:p.Val603Ile
NP_001393704.1:p.Val536Ile
NP_001393705.1:p.Val536Ile
NP_001393706.1:p.Val536Ile
NP_001393707.1:p.Val536Ile
NP_001393708.1:p.Val479Ile
NP_001393709.1:p.Val479Ile
NP_001393710.1:p.Val479Ile
NP_001393711.1:p.Val479Ile
NP_001393712.1:p.Val436Ile
NP_001393713.1:p.Val448Ile
NP_001393714.1:p.Val439Ile
NP_001393715.1:p.Val436Ile
NP_001393716.1:p.Val434Ile
NP_001393717.1:p.Val383Ile
NP_001393718.1:p.Val383Ile
NP_001393719.1:p.Val383Ile
NP_001393720.1:p.Val343Ile
NP_001393721.1:p.Val295Ile
NP_001393722.1:p.Val295Ile
NP_001393723.1:p.Val295Ile
NP_065680.1:p.Val778Ile
NP_065681.1:p.Val778Ile
NP_065681.1:p.Val778Ile
NP_065681.1:p.Val778Ile
NP_066124.1:p.Val778Ile
NP_066124.1:p.Val778Ile
LRG_518t1:c.2332G>A
LRG_518t2:c.2332G>A
LRG_518:g.46352G>A
LRG_518p1:p.Val778Ile
LRG_518p2:p.Val778Ile
NC_000010.10:g.43613868G>A
NM_001355216.1:c.1570G>A
NM_020630.4:c.2332G>A
NM_020630.6:c.2332G>A
NM_020975.4:c.2332G>A
P07949:p.Val778Ile

Protein change:

V295I; VAL778ILE

Links:

UniProtKB: P07949#VAR_044395; OMIM: 164761.0053; dbSNP: rs75686697

NCBI 1000 Genomes Browser:

rs75686697

Molecular consequence:

NM_000323.2:c.2332G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1570G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.2332G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.2332G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.2332G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.2332G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.2203G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.2203G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.2197G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.2203G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.2197G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.2044G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.2044G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.2068G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1936G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.2044G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1894G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1936G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1894G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1807G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1606G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1606G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1606G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1606G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1435G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1435G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1435G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1435G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.1306G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1342G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.1306G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.1300G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.1147G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.1147G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.1147G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.1027G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.2332G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.2332G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.2332G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Renal hypodysplasia/aplasia 1 (RHDA1)
Synonyms:: HEREDITARY RENAL APLASIA; RENAL APLASIA; Urogenital adysplasia, hereditary
Identifiers:: MONDO: MONDO:0024519; MedGen: C1619700; Orphanet: 411709; OMIM: 191830

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gi|289064441|gb|GU256835.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035239	OMIM	no assertion criteria provided	Uncertain significance (Feb 1, 2008)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001265261	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035239

OMIM

no assertion criteria provided

Uncertain significance
(Feb 1, 2008)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001265261

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Renal aplasia in humans is associated with RET mutations.

Skinner MA, Safford SD, Reeves JG, Jackson ME, Freemerman AJ.

Am J Hum Genet. 2008 Feb;82(2):344-51. doi: 10.1016/j.ajhg.2007.10.008. Epub 2008 Jan 31.

PubMed [citation]

PMID:: 18252215
PMCID:: PMC2427293

Details of each submission

From OMIM, SCV000035239.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

This variant, previously titled RENAL AGENESIS, has been reclassified as a variant of unknown significance because its contribution to renal agenesis (see 191830) has not been confirmed.

In paraffin-embedded tissue samples from 2 unrelated stillborn fetuses with bilateral renal agenesis, Skinner et al. (2008) identified a heterozygous G-to-A transition in exon 13 of the RET gene, resulting in a val778-to-ile (V778I) substitution. One of the fetuses also carried a RET M918T mutation (164761.0013). Parental DNA was not studied. In vitro functional expression studies showed that the V788I mutant protein was constitutively phosphorylated at tyrosine 1062. Skinner et al. (2008) postulated a RET signaling defect resulting in loss of function. The fetuses did not have evidence of Hirschsprung disease (142623), MEN2A (171400), MEN2B (162300), or familial medullary thyroid carcinoma (155240). However, Skinner et al. (2008) noted that these conditions generally present with clinical findings later in childhood; they may have been present in the fetus and not detected by standard autopsy.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001265261.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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