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.
ClinVar Genomic variation as it relates to human health
NM_024529.5(CDC73):c.1333G>A (p.Val445Ile)
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.
(11)
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.
Conflicting classifications of pathogenicity
Uncertain significance(8); Likely benign(1)
Uncertain significance(8); Likely benign(1)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024529.5(CDC73):c.1333G>A (p.Val445Ile)
Variation ID: 241494 Accession: VCV000241494.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q31.2 1: 193236272 (GRCh38) [ NCBI UCSC ] 1: 193205402 (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 Oct 10, 2018 Sep 29, 2024 May 14, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024529.5:c.1333G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078805.3:p.Val445Ile missense NC_000001.11:g.193236272G>A NC_000001.10:g.193205402G>A NG_012691.1:g.119315G>A LRG_507:g.119315G>A LRG_507t1:c.1333G>A LRG_507p1:p.Val445Ile - Protein change
- V445I
- Other names
- -
- Canonical SPDI
- NC_000001.11:193236271:G:A
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- 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. |
|||
| CDC73 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1600 | 1654 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 27, 2024 | RCV000228358.15 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 11, 2022 | RCV001011102.3 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 28, 2021 | RCV001099302.7 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 2, 2024 | RCV001101291.5 | |
| Uncertain significance (3) |
criteria provided, single submitter
|
May 14, 2024 | RCV001580090.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 23, 2021 | RCV002487085.1 |
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
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperparathyroidism 2 with jaw tumors
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001255747.1
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
Method: clinical testing
|
Parathyroid carcinoma
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001255746.1
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
Method: clinical testing
|
Hyperparathyroidism 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001257891.1
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 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Parathyroid carcinoma
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000290766.10
First in ClinVar: Jul 02, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 445 of the CDC73 protein (p.Val445Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 445 of the CDC73 protein (p.Val445Ile). This variant is present in population databases (rs368442389, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CDC73-related conditions. ClinVar contains an entry for this variant (Variation ID: 241494). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDC73 protein function with a positive predictive value of 80%. 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)
|
|
|
Likely benign
(Feb 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001171384.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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)
|
|
|
Uncertain significance
(Oct 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperparathyroidism 2 with jaw tumors
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002012438.2
First in ClinVar: Nov 11, 2021 Last updated: Dec 24, 2022 |
Comment:
The CDC73 c.1333G>A (p.Val445Ile) missense change has a maximum subpopulation frequency of 0.0085% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-193205402-G-A). In silico tools are not in agreement about … (more)
The CDC73 c.1333G>A (p.Val445Ile) missense change has a maximum subpopulation frequency of 0.0085% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-193205402-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). The variant has been identified in 1 of 1358 control individuals collected as part of non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with hyperparathyroidism-jaw tumor syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP2. (less)
|
|
|
Uncertain significance
(Aug 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperparathyroidism 1
Hyperparathyroidism 2 with jaw tumors Parathyroid carcinoma
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002782322.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Feb 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperparathyroidism 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005060038.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(May 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001987801.4
First in ClinVar: Nov 06, 2021 Last updated: Sep 29, 2024 |
Comment:
In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in unaffected control subjects, but not observed in any cases in … (more)
In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in unaffected control subjects, but not observed in any cases in a melanoma/multiple primary cancer study (PMID: 29641532); This variant is associated with the following publications: (PMID: 15923622, 29641532) (less)
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809639.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975748.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
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Comment:
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 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 sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 445 of the CDC73 protein (p.Val445Ile). This variant is present in population databases (rs368442389, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CDC73-related conditions. ClinVar contains an entry for this variant (Variation ID: 241494). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDC73 protein function with a positive predictive value of 80%. 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 alteration is classified as likely 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.
Comment:
The CDC73 c.1333G>A (p.Val445Ile) missense change has a maximum subpopulation frequency of 0.0085% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-193205402-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). The variant has been identified in 1 of 1358 control individuals collected as part of non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with hyperparathyroidism-jaw tumor syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP2.
Comment:
In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in unaffected control subjects, but not observed in any cases in a melanoma/multiple primary cancer study (PMID: 29641532); This variant is associated with the following publications: (PMID: 15923622, 29641532)
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:
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 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 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 sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 445 of the CDC73 protein (p.Val445Ile). This variant is present in population databases (rs368442389, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CDC73-related conditions. ClinVar contains an entry for this variant (Variation ID: 241494). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDC73 protein function with a positive predictive value of 80%. 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 alteration is classified as likely 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.
Comment:
The CDC73 c.1333G>A (p.Val445Ile) missense change has a maximum subpopulation frequency of 0.0085% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-193205402-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). The variant has been identified in 1 of 1358 control individuals collected as part of non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with hyperparathyroidism-jaw tumor syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP2.
Comment:
In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in unaffected control subjects, but not observed in any cases in a melanoma/multiple primary cancer study (PMID: 29641532); This variant is associated with the following publications: (PMID: 15923622, 29641532)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. | Pritchard AL | PloS one | 2018 | PMID: 29641532 |
Text-mined citations for rs368442389 ...
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.