VCV000548897.23 - ClinVar

NM_020975.6(RET):c.1649-4G>A

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.

(9)

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.

Conflicting classifications of pathogenicity
Uncertain significance(5); Benign(1); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020975.6(RET):c.1649-4G>A

Variation ID: 548897 Accession: VCV000548897.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43112849 (GRCh38) [ NCBI UCSC ] 10: 43608297 (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	Jul 15, 2018	Aug 4, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.1649-4G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001355216.2:c.887-4G>A		intron variant
NM_001406743.1:c.1649-4G>A		intron variant
NM_001406744.1:c.1649-4G>A		intron variant
NM_001406759.1:c.1649-4G>A		intron variant
NM_001406760.1:c.1649-4G>A		intron variant
NM_001406761.1:c.1520-4G>A		intron variant
NM_001406762.1:c.1520-4G>A		intron variant
NM_001406763.1:c.1649-4G>A		intron variant
NM_001406764.1:c.1520-4G>A		intron variant
NM_001406765.1:c.1649-4G>A		intron variant
NM_001406766.1:c.1361-4G>A		intron variant
NM_001406767.1:c.1361-4G>A		intron variant
NM_001406768.1:c.1520-4G>A		intron variant
NM_001406769.1:c.1253-4G>A		intron variant
NM_001406770.1:c.1361-4G>A		intron variant
NM_001406771.1:c.1211-4G>A		intron variant
NM_001406772.1:c.1253-4G>A		intron variant
NM_001406773.1:c.1211-4G>A		intron variant
NM_001406774.1:c.1124-4G>A		intron variant
NM_001406775.1:c.923-4G>A		intron variant
NM_001406776.1:c.923-4G>A		intron variant
NM_001406777.1:c.923-4G>A		intron variant
NM_001406778.1:c.923-4G>A		intron variant
NM_001406779.1:c.752-4G>A		intron variant
NM_001406780.1:c.752-4G>A		intron variant
NM_001406781.1:c.752-4G>A		intron variant
NM_001406782.1:c.752-4G>A		intron variant
NM_001406783.1:c.623-4G>A		intron variant
NM_001406784.1:c.659-4G>A		intron variant
NM_001406785.1:c.752-4G>A		intron variant
NM_001406786.1:c.623-4G>A		intron variant
NM_001406787.1:c.752-4G>A		intron variant
NM_001406788.1:c.464-4G>A		intron variant
NM_001406789.1:c.464-4G>A		intron variant
NM_001406790.1:c.464-4G>A		intron variant
NM_001406791.1:c.464-4G>A		intron variant
NM_001406792.1:c.200-4G>A		intron variant
NM_001406793.1:c.200-4G>A		intron variant
NM_001406794.1:c.200-4G>A		intron variant
NM_020630.7:c.1649-4G>A		intron variant
NC_000010.11:g.43112849G>A
NC_000010.10:g.43608297G>A
NG_007489.1:g.40781G>A
LRG_518:g.40781G>A
LRG_518t1:c.1649-4G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000010.11:43112848:G:A

Functional
consequence

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

Global minor allele
frequency (GMAF)

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

The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

dbSNP: rs369769303

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	3580	3702

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.
Multiple endocrine neoplasia type 2A	Likely benign (1)	criteria provided, single submitter	May 1, 2018	RCV000663217.2
Multiple endocrine neoplasia, type 2	Likely benign (1)	criteria provided, single submitter	Jan 21, 2024	RCV000862007.10
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Nov 12, 2023	RCV001012564.5
Hirschsprung disease, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001104474.5
Renal hypodysplasia/aplasia 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001104475.5
Multiple endocrine neoplasia	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001104476.5
Pheochromocytoma	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001104477.5
not provided	Likely benign (1)	criteria provided, single submitter	Apr 1, 2024	RCV004546550.4

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.
Likely benign (May 01, 2018)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000786403.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018
Uncertain significance (Jan 13, 2018)	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: SCV001261341.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	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: SCV001261344.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	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: SCV001261342.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	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: SCV001261343.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (May 25, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529939.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The RET c.1649-4G>A variant has not been reported in the literature to our knowledge. It was observed in 3/10336 chromosomes of the Ashkenazi Jewish subpopulation … (more) The RET c.1649-4G>A variant has not been reported in the literature to our knowledge. It was observed in 3/10336 chromosomes of the Ashkenazi Jewish subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org). The variant has been reported in ClinVar (Variation ID 548897). This variant involves a nucleotide that is not conserved, and in silico tools suggest that the variant does not impact splicing, though these predictions have not been confirmed by functional studies. There is no indication that this variant causes disease, but the evidence is insufficient currently to prove that conclusively. Thus, the clinical significance of this variant is currently uncertain. (less)
Likely benign (Jan 21, 2024)	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: SCV001002434.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Benign (Nov 12, 2023)	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: SCV001173032.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005042383.4 First in ClinVar: May 12, 2024 Last updated: Aug 04, 2024	Comment: RET: BP4 Number of individuals with the variant: 1

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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 rs369769303 ...

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.1649-4G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs369769303 ...