VCV000877094.11 - ClinVar

NM_020975.6(RET):c.1601T>C (p.Leu534Pro)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020975.6(RET):c.1601T>C (p.Leu534Pro)

Variation ID: 877094 Accession: VCV000877094.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43112177 (GRCh38) [ NCBI UCSC ] 10: 43607625 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 31, 2020	Jun 17, 2024	Feb 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.1601T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Leu534Pro	missense
NM_000323.2:c.1601T>C	NP_000314.1:p.Leu534Pro	missense
NM_001355216.2:c.839T>C	NP_001342145.1:p.Leu280Pro	missense
NM_001406743.1:c.1601T>C	NP_001393672.1:p.Leu534Pro	missense
NM_001406744.1:c.1601T>C	NP_001393673.1:p.Leu534Pro	missense
NM_001406759.1:c.1601T>C	NP_001393688.1:p.Leu534Pro	missense
NM_001406760.1:c.1601T>C	NP_001393689.1:p.Leu534Pro	missense
NM_001406761.1:c.1472T>C	NP_001393690.1:p.Leu491Pro	missense
NM_001406762.1:c.1472T>C	NP_001393691.1:p.Leu491Pro	missense
NM_001406763.1:c.1601T>C	NP_001393692.1:p.Leu534Pro	missense
NM_001406764.1:c.1472T>C	NP_001393693.1:p.Leu491Pro	missense
NM_001406765.1:c.1601T>C	NP_001393694.1:p.Leu534Pro	missense
NM_001406766.1:c.1313T>C	NP_001393695.1:p.Leu438Pro	missense
NM_001406767.1:c.1313T>C	NP_001393696.1:p.Leu438Pro	missense
NM_001406768.1:c.1472T>C	NP_001393697.1:p.Leu491Pro	missense
NM_001406769.1:c.1205T>C	NP_001393698.1:p.Leu402Pro	missense
NM_001406770.1:c.1313T>C	NP_001393699.1:p.Leu438Pro	missense
NM_001406771.1:c.1163T>C	NP_001393700.1:p.Leu388Pro	missense
NM_001406772.1:c.1205T>C	NP_001393701.1:p.Leu402Pro	missense
NM_001406773.1:c.1163T>C	NP_001393702.1:p.Leu388Pro	missense
NM_001406774.1:c.1076T>C	NP_001393703.1:p.Leu359Pro	missense
NM_001406775.1:c.875T>C	NP_001393704.1:p.Leu292Pro	missense
NM_001406776.1:c.875T>C	NP_001393705.1:p.Leu292Pro	missense
NM_001406777.1:c.875T>C	NP_001393706.1:p.Leu292Pro	missense
NM_001406778.1:c.875T>C	NP_001393707.1:p.Leu292Pro	missense
NM_001406779.1:c.704T>C	NP_001393708.1:p.Leu235Pro	missense
NM_001406780.1:c.704T>C	NP_001393709.1:p.Leu235Pro	missense
NM_001406781.1:c.704T>C	NP_001393710.1:p.Leu235Pro	missense
NM_001406782.1:c.704T>C	NP_001393711.1:p.Leu235Pro	missense
NM_001406783.1:c.575T>C	NP_001393712.1:p.Leu192Pro	missense
NM_001406784.1:c.611T>C	NP_001393713.1:p.Leu204Pro	missense
NM_001406785.1:c.704T>C	NP_001393714.1:p.Leu235Pro	missense
NM_001406786.1:c.575T>C	NP_001393715.1:p.Leu192Pro	missense
NM_001406787.1:c.704T>C	NP_001393716.1:p.Leu235Pro	missense
NM_001406788.1:c.416T>C	NP_001393717.1:p.Leu139Pro	missense
NM_001406789.1:c.416T>C	NP_001393718.1:p.Leu139Pro	missense
NM_001406790.1:c.416T>C	NP_001393719.1:p.Leu139Pro	missense
NM_001406791.1:c.416T>C	NP_001393720.1:p.Leu139Pro	missense
NM_001406792.1:c.152T>C	NP_001393721.1:p.Leu51Pro	missense
NM_001406793.1:c.152T>C	NP_001393722.1:p.Leu51Pro	missense
NM_001406794.1:c.152T>C	NP_001393723.1:p.Leu51Pro	missense
NM_020629.2:c.1601T>C	NP_065680.1:p.Leu534Pro	missense
NM_020630.7:c.1601T>C	NP_065681.1:p.Leu534Pro	missense
NC_000010.11:g.43112177T>C
NC_000010.10:g.43607625T>C
NG_007489.1:g.40109T>C
LRG_518:g.40109T>C
LRG_518t1:c.1601T>C	LRG_518p1:p.Leu534Pro
LRG_518t2:c.1601T>C	LRG_518p2:p.Leu534Pro

... more HGVS ... less HGVS

Protein change

L534P, L280P, L359P, L402P, L491P, L192P, L235P, L438P, L51P, L139P, L204P, L292P, L388P

Other names

Canonical SPDI

NC_000010.11:43112176:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

dbSNP: rs1206429429 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RET		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3598	3720

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Renal hypodysplasia/aplasia 1	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001102552.6
Multiple endocrine neoplasia	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001102553.6
Hirschsprung disease, susceptibility to, 1	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 10, 2024	RCV001102554.7
Pheochromocytoma	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001102555.6
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 15, 2021	RCV002402498.2
Multiple endocrine neoplasia, type 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 4, 2023	RCV003645886.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001259235.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Renal hypodysplasia/aplasia 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001259233.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Multiple endocrine neoplasia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001259234.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Pheochromocytoma Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001259236.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: 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, … (more) 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. (less)
Uncertain significance (Dec 20, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple endocrine neoplasia, type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004526284.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: 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 … (more) 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 877094). This variant has not been reported in the literature in individuals affected with RET-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 534 of the RET protein (p.Leu534Pro). (less)
Uncertain Significance (Mar 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia, type 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004817875.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 1
Uncertain significance (Jun 15, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002707880.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.L534P variant (also known as c.1601T>C), located in coding exon 8 of the RET gene, results from a T to C substitution at nucleotide … (more) The p.L534P variant (also known as c.1601T>C), located in coding exon 8 of the RET gene, results from a T to C substitution at nucleotide position 1601. The leucine at codon 534 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005054193.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

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.

Comment:

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 877094). This variant has not been reported in the literature in individuals affected with RET-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 534 of the RET protein (p.Leu534Pro).

Comment:

The p.L534P variant (also known as c.1601T>C), located in coding exon 8 of the RET gene, results from a T to C substitution at nucleotide position 1601. The leucine at codon 534 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1206429429 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.1601T>C (p.Leu534Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1206429429 ...