ClinVar Genomic variation as it relates to human health
NM_001126128.2(PROK2):c.297dup (p.Gly100fs)
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.
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.
Pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001126128.2(PROK2):c.297dup (p.Gly100fs)
Variation ID: 420068 Accession: VCV000420068.7
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 3p13 3: 71772816-71772817 (GRCh38) [ NCBI UCSC ] 3: 71821967-71821968 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 27, 2017 Feb 28, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001126128.2:c.297dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119600.1:p.Gly100fs frameshift NM_001126128.2:c.297dupT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001126128.1:c.297dupT NM_021935.4:c.234dup NP_068754.1:p.Gly79fs frameshift NC_000003.12:g.71772822dup NC_000003.11:g.71821973dup NG_008275.1:g.17390dup - Protein change
- G100fs, G79fs
- Other names
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- Canonical SPDI
- NC_000003.12:71772816:AAAAAA:AAAAAAA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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PROK2 | - | - |
GRCh38 GRCh37 |
60 | 79 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 21, 2024 | RCV000486838.4 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 20, 2006 | RCV002295299.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 3, 2023 | RCV003401531.1 | |
PROK2-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Aug 10, 2023 | RCV003419793.5 |
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
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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
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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
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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. |
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Uncertain significance
(Nov 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568572.3
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
Reported previously using alternate nomenclature (c.234_235insT) in the heterozygous state in one family with Kallmann syndrome, however, the family underwent sequencing for only two genes … (more)
Reported previously using alternate nomenclature (c.234_235insT) in the heterozygous state in one family with Kallmann syndrome, however, the family underwent sequencing for only two genes (Dode et al., 2006). Of the five family members heterozygous for the c.297dupT variant, one had anosmia only, another had hypogonadism only, two individuals had both hypogonadism and anosmia, and one individual was unaffected.; Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost and replaced with 21 incorrect amino acids; This variant is associated with the following publications: (PMID: 31200363, 17054399) (less)
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Uncertain significance
(Jun 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501509.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Uncertain significance
(Aug 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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PROK2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004117541.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PROK2 c.297dupT variant is predicted to result in a frameshift and premature protein termination (p.Gly100Trpfs*22). This variant is located in the last exon of … (more)
The PROK2 c.297dupT variant is predicted to result in a frameshift and premature protein termination (p.Gly100Trpfs*22). This variant is located in the last exon of PROK2, is not predicted to undergo nonsense mediated decay, and disrupts the final ~30 amino acids. This variant, also referred to as c.234_235insT (p.Asn79fs*100), has been reported in the heterozygous state in three siblings presenting with Kallmann syndrome; it was inherited from their affected mother and was also present in an asymptomatic sister (Dodé et al. 2006. PubMed ID: 17054399, Family E). This variant has also been reported in the homozygous (Patient #6) and heterozygous (Patient #45) state in individuals with Kallmann syndrome (Amato et al. 2019. PubMed ID: 31200363). This variant is observed in 31 out of ~282,370 alleles in a large population database (http://gnomad.broadinstitute.org/variant/3-71821967-C-CA). This variant has conflicting interpretations of pathogenicity of uncertain and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/420068/). A premature protein termination variant (p.Arg122*) downstream of the one reported here has been reported in a patient with Kallmann syndrome (Sarfati et al. 2013. PubMed ID: 24031091). Although we suspect that this variant may be pathogenic, possibly for an autosomal recessive form of disease, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122042.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: PROK2 c.297dupT (p.Gly100TrpfsX22), located in the last exon of the gene, results in a premature termination codon and is predicted to cause a … (more)
Variant summary: PROK2 c.297dupT (p.Gly100TrpfsX22), located in the last exon of the gene, results in a premature termination codon and is predicted to cause a truncation of the encoded protein, but is not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 0.00011 in 251124 control chromosomes (gnomAD). c.297dupT has been reported in the literature in heterozygous and homozygous individuals affected with Kallmann Syndrome/Hypogonadotropic Hypogonadism 4 With Or Without Anosmia (e.g. Dode_2006, Abreu_2008, Amato_2019). In one family with a history of anosmia, the variant was found in the heterozygous state in five individuals, two with hypogonadism and anosmia, one with only hypogonadism, one with only anosmia, and one who was unaffected (Dode_2006). In another study, the variant was found in the homozygous state in two brothers with Kallmann Syndrome, although the parents were unavailable for testing and were reportedly unaffected (Abreu_2008). In both studies, only several genes related to the phenotype were sequenced. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Kallmann Syndrome/Hypogonadotropic Hypogonadism 4 With Or Without Anosmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31200363, 17054399, 20022991, 18682503). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Pathogenic
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004675443.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly100Trpfs*22) in the PROK2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gly100Trpfs*22) in the PROK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PROK2 protein. This variant is present in population databases (rs768413190, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with clinical features of Kallmann Syndrome (PMID: 17054399, 31200363). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 420068). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 20, 2006)
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no assertion criteria provided
Method: literature only
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HYPOGONADOTROPIC HYPOGONADISM 4 WITH ANOSMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023950.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 24, 2013 |
Comment on evidence:
In affected members of a family with manifestations of Kallmann syndrome-4 (HH4; 610628) in 4 generations, Dode et al. (2006) identified heterozygosity for a 1-nucleotide … (more)
In affected members of a family with manifestations of Kallmann syndrome-4 (HH4; 610628) in 4 generations, Dode et al. (2006) identified heterozygosity for a 1-nucleotide insertion, a T between nucleotides 234 and 235, in exon 4 of the PROK2 gene, predicted to result in a frameshift at codon 79 with a premature termination at codon 100 (79fsX100). The most recent generation of the family had 2 sisters with full Kallmann syndrome, a brother with hypogonadism only, and 3 unaffected sisters. The mother, maternal grandfather, and great grandfather had anosmia only. The mutation was not found in 500 alleles from ethnically matched (Caucasian) control individuals. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism. | Amato LGL | European journal of endocrinology | 2019 | PMID: 31200363 |
A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. | Sarfati J | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20022991 |
Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. | Abreu AP | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 18682503 |
Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. | Dodé C | PLoS genetics | 2006 | PMID: 17054399 |
Text-mined citations for rs768413190 ...
HelpRecord last updated Jun 23, 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.