VCV001008125.14 - ClinVar

NM_020975.6(RET):c.1828A>C (p.Asn610His)

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.

(5)

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.1828A>C (p.Asn610His)

Variation ID: 1008125 Accession: VCV001008125.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43113624 (GRCh38) [ NCBI UCSC ] 10: 43609072 (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	Mar 7, 2021	Jun 17, 2024	May 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.1828A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Asn610His	missense
NM_000323.2:c.1828A>C	NP_000314.1:p.Asn610His	missense
NM_001355216.2:c.1066A>C	NP_001342145.1:p.Asn356His	missense
NM_001406743.1:c.1828A>C	NP_001393672.1:p.Asn610His	missense
NM_001406744.1:c.1828A>C	NP_001393673.1:p.Asn610His	missense
NM_001406759.1:c.1828A>C	NP_001393688.1:p.Asn610His	missense
NM_001406760.1:c.1828A>C	NP_001393689.1:p.Asn610His	missense
NM_001406761.1:c.1699A>C	NP_001393690.1:p.Asn567His	missense
NM_001406762.1:c.1699A>C	NP_001393691.1:p.Asn567His	missense
NM_001406763.1:c.1828A>C	NP_001393692.1:p.Asn610His	missense
NM_001406764.1:c.1699A>C	NP_001393693.1:p.Asn567His	missense
NM_001406765.1:c.1828A>C	NP_001393694.1:p.Asn610His	missense
NM_001406766.1:c.1540A>C	NP_001393695.1:p.Asn514His	missense
NM_001406767.1:c.1540A>C	NP_001393696.1:p.Asn514His	missense
NM_001406768.1:c.1699A>C	NP_001393697.1:p.Asn567His	missense
NM_001406769.1:c.1432A>C	NP_001393698.1:p.Asn478His	missense
NM_001406770.1:c.1540A>C	NP_001393699.1:p.Asn514His	missense
NM_001406771.1:c.1390A>C	NP_001393700.1:p.Asn464His	missense
NM_001406772.1:c.1432A>C	NP_001393701.1:p.Asn478His	missense
NM_001406773.1:c.1390A>C	NP_001393702.1:p.Asn464His	missense
NM_001406774.1:c.1303A>C	NP_001393703.1:p.Asn435His	missense
NM_001406775.1:c.1102A>C	NP_001393704.1:p.Asn368His	missense
NM_001406776.1:c.1102A>C	NP_001393705.1:p.Asn368His	missense
NM_001406777.1:c.1102A>C	NP_001393706.1:p.Asn368His	missense
NM_001406778.1:c.1102A>C	NP_001393707.1:p.Asn368His	missense
NM_001406779.1:c.931A>C	NP_001393708.1:p.Asn311His	missense
NM_001406780.1:c.931A>C	NP_001393709.1:p.Asn311His	missense
NM_001406781.1:c.931A>C	NP_001393710.1:p.Asn311His	missense
NM_001406782.1:c.931A>C	NP_001393711.1:p.Asn311His	missense
NM_001406783.1:c.802A>C	NP_001393712.1:p.Asn268His	missense
NM_001406784.1:c.838A>C	NP_001393713.1:p.Asn280His	missense
NM_001406786.1:c.802A>C	NP_001393715.1:p.Asn268His	missense
NM_001406787.1:c.931A>C	NP_001393716.1:p.Asn311His	missense
NM_001406788.1:c.643A>C	NP_001393717.1:p.Asn215His	missense
NM_001406789.1:c.643A>C	NP_001393718.1:p.Asn215His	missense
NM_001406790.1:c.643A>C	NP_001393719.1:p.Asn215His	missense
NM_001406792.1:c.379A>C	NP_001393721.1:p.Asn127His	missense
NM_001406793.1:c.379A>C	NP_001393722.1:p.Asn127His	missense
NM_001406794.1:c.379A>C	NP_001393723.1:p.Asn127His	missense
NM_020629.2:c.1828A>C	NP_065680.1:p.Asn610His	missense
NM_020630.7:c.1828A>C	NP_065681.1:p.Asn610His	missense
NC_000010.11:g.43113624A>C
NC_000010.10:g.43609072A>C
NG_007489.1:g.41556A>C
LRG_518:g.41556A>C
LRG_518t1:c.1828A>C	LRG_518p1:p.Asn610His
LRG_518t2:c.1828A>C	LRG_518p2:p.Asn610His

... more HGVS ... less HGVS

Protein change

N356H, N610H, N280H, N464H, N127H, N215H, N268H, N435H, N478H, N514H, N311H, N368H, N567H

Other names

Canonical SPDI

NC_000010.11:43113623:A: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.

Links

dbSNP: rs1837994023 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	3593	3715

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 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 4, 2023	RCV001305413.10
Hirschsprung disease, susceptibility to, 1 Multiple endocrine neoplasia type 2A	not provided (1)	no classification provided	-	RCV001824949.3
Hirschsprung disease, susceptibility to, 1 Multiple endocrine neoplasia type 2A Multiple endocrine neoplasia type 2B	not provided (1)	no classification provided	-	RCV001535690.3
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Feb 12, 2021	RCV002411977.2

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 (Jul 24, 2020)	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: SCV001494748.4 First in ClinVar: Mar 07, 2021 Last updated: Feb 20, 2024	Comment: This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with histidine at codon 610 of the RET protein … (more) This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with histidine at codon 610 of the RET protein (p.Asn610His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. (less)
Uncertain Significance (May 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: SCV004824665.1 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)	Comment: This missense variant replaces asparagine with histidine at codon 610 of the RET protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces asparagine with histidine at codon 610 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 1
Uncertain significance (Feb 12, 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: SCV002711124.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.N610H variant (also known as c.1828A>C), located in coding exon 10 of the RET gene, results from an A to C substitution at nucleotide … (more) The p.N610H variant (also known as c.1828A>C), located in coding exon 10 of the RET gene, results from an A to C substitution at nucleotide position 1828. The asparagine at codon 610 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
not provided (-)	no classification provided Method: phenotyping only	Multiple endocrine neoplasia type 2A Hirschsprung disease, susceptibility to, 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074996.2 First in ClinVar: Feb 12, 2022 Last updated: Jun 17, 2024	Comment: Variant interpreted as Uncertain significance and reported on 07-24-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the … (more) Variant interpreted as Uncertain significance and reported on 07-24-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Myopia (present) , Bipolar affective disorder (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Short attention span (present) , Abnormality of … (more) Myopia (present) , Bipolar affective disorder (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Short attention span (present) , Abnormality of facial musculature (present) , Abnormal muscle physiology (present) , Abnormal EKG (present) , Hypertensive disorder (present) , Hypercholesterolemia (present) , Asthma (present) , Abnormality of the liver (present) , Abnormal intestine morphology (present) , Abnormality of the bladder (present) , Cervical cancer (present) , Breast carcinoma (present) , Ovarian neoplasm (present) , Neoplasm of uterus (present) , Colon cancer (present) , Bladder neoplasm (present) , Renal neoplasm (present) (less) Indication for testing: Presymptomatic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-07-24 Testing laboratory interpretation: Uncertain significance
not provided (-)	no classification provided Method: phenotyping only	Multiple endocrine neoplasia type 2A Multiple endocrine neoplasia type 2B Hirschsprung disease, susceptibility to, 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749766.2 First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024	Comment: Variant interpreted as Uncertain significance and reported on 07-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Uncertain significance and reported on 07-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Neoplasm of uterine cervix (present) Indication for testing: Presymptomatic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-07-24 Testing laboratory interpretation: Uncertain significance

Comment:

This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with histidine at codon 610 of the RET protein (p.Asn610His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

Comment:

This missense variant replaces asparagine with histidine at codon 610 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The p.N610H variant (also known as c.1828A>C), located in coding exon 10 of the RET gene, results from an A to C substitution at nucleotide position 1828. The asparagine at codon 610 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Variant interpreted as Uncertain significance and reported on 07-24-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Comment:

Variant interpreted as Uncertain significance and reported on 07-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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 rs1837994023 ...

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.1828A>C (p.Asn610His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1837994023 ...