The NTHL1 c.746A>G (p.Lys249Arg) missense change has a maximum subpopulation frequency of 0.022% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with NTHL1-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_002528.7(NTHL1):c.746A>G (p.Lys249Arg)
Germline
Classification
Help
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)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002528.7(NTHL1):c.746A>G (p.Lys249Arg)
Variation ID: 659005 Accession: VCV000659005.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2040178 (GRCh38) [ NCBI UCSC ] 16: 2090179 (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 Aug 14, 2019 Sep 29, 2024 Jul 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002528.7:c.746A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002519.2:p.Lys249Arg missense NM_001318193.2:c.575A>G NP_001305122.2:p.Lys192Arg missense NM_001318194.2:c.416A>G NP_001305123.1:p.Lys139Arg missense NC_000016.10:g.2040178T>C NC_000016.9:g.2090179T>C NG_008412.1:g.12689A>G NG_047104.1:g.18311T>C LRG_1366:g.12689A>G LRG_1366t1:c.746A>G LRG_1366p1:p.Lys249Arg - Protein change
- K192R, K139R, K249R
- Other names
- -
- Canonical SPDI
- NC_000016.10:2040177:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00011
Exome Aggregation Consortium (ExAC) 0.00012
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| NTHL1 | - | - |
GRCh38 GRCh37 |
1522 | 1643 | |
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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 2, 2024 | RCV000815936.13 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 20, 2022 | RCV001026740.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 31, 2024 | RCV002268308.8 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV003153857.3 |
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
(Sep 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529014.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The NTHL1 c.770A>G (p.K257R) variant has not been reported in the literature to our knowledge. It was observed in 29/129038 chromosomes of the Non-Finnish European … (more)
The NTHL1 c.770A>G (p.K257R) variant has not been reported in the literature to our knowledge. It was observed in 29/129038 chromosomes of the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 659005). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Jan 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003843002.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
The NTHL1 c.746A>G (p.Lys249Arg) missense change has a maximum subpopulation frequency of 0.022% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more)
The NTHL1 c.746A>G (p.Lys249Arg) missense change has a maximum subpopulation frequency of 0.022% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with NTHL1-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
|
|
|
Uncertain significance
(Aug 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222227.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33980861 (2021)) and cholestatic liver disease (PMID: 37353797 (2023)). The … (more)
In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33980861 (2021)) and cholestatic liver disease (PMID: 37353797 (2023)). The frequency of this variant in the general population, 0.00046 (12/26128 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000956416.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 257 of the NTHL1 protein (p.Lys257Arg). … (more)
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 257 of the NTHL1 protein (p.Lys257Arg). This variant is present in population databases (rs373067940, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 33980861). ClinVar contains an entry for this variant (Variation ID: 659005). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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
(Oct 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001189178.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.K257R variant (also known as c.770A>G), located in coding exon 5 of the NTHL1 gene, results from an A to G substitution at nucleotide … (more)
The p.K257R variant (also known as c.770A>G), located in coding exon 5 of the NTHL1 gene, results from an A to G substitution at nucleotide position 770. The lysine at codon 257 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Mar 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005053718.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551593.7
First in ClinVar: Jul 28, 2022 Last updated: Aug 04, 2024 |
|
|
|
Uncertain significance
(Jul 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001793628.4
First in ClinVar: Aug 21, 2021 Last updated: Sep 29, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and also in unaffected … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and also in unaffected controls (PMID: 33980861); This variant is associated with the following publications: (PMID: 33980861, 37353797) (less)
|
Comment:
Comment:
In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33980861 (2021)) and cholestatic liver disease (PMID: 37353797 (2023)). The frequency of this variant in the general population, 0.00046 (12/26128 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 257 of the NTHL1 protein (p.Lys257Arg). This variant is present in population databases (rs373067940, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 33980861). ClinVar contains an entry for this variant (Variation ID: 659005). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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:
The p.K257R variant (also known as c.770A>G), located in coding exon 5 of the NTHL1 gene, results from an A to G substitution at nucleotide position 770. The lysine at codon 257 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and also in unaffected controls (PMID: 33980861); This variant is associated with the following publications: (PMID: 33980861, 37353797)
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:
The NTHL1 c.746A>G (p.Lys249Arg) missense change has a maximum subpopulation frequency of 0.022% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with NTHL1-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Comment:
In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33980861 (2021)) and cholestatic liver disease (PMID: 37353797 (2023)). The frequency of this variant in the general population, 0.00046 (12/26128 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 257 of the NTHL1 protein (p.Lys257Arg). This variant is present in population databases (rs373067940, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 33980861). ClinVar contains an entry for this variant (Variation ID: 659005). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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:
The p.K257R variant (also known as c.770A>G), located in coding exon 5 of the NTHL1 gene, results from an A to G substitution at nucleotide position 770. The lysine at codon 257 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and also in unaffected controls (PMID: 33980861); This variant is associated with the following publications: (PMID: 33980861, 37353797)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD). | Pinto E Vairo F | Journal of translational medicine | 2023 | PMID: 37353797 |
| Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects. | Li N | NPJ breast cancer | 2021 | PMID: 33980861 |
Text-mined citations for rs373067940 ...
HelpThese 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 Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.