VCV001029341.9 - ClinVar

NM_001145860.2(POP1):c.1537C>T (p.Arg513Ter)

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.

(6)

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
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001145860.2(POP1):c.1537C>T (p.Arg513Ter)

Variation ID: 1029341 Accession: VCV001029341.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q22.2 8: 98140831 (GRCh38) [ NCBI UCSC ] 8: 99153059 (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 22, 2021	May 1, 2024	Oct 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001145860.2:c.1537C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001139332.1:p.Arg513Ter	nonsense
NM_001145861.2:c.1537C>T	NP_001139333.1:p.Arg513Ter	nonsense
NM_015029.3:c.1537C>T	NP_055844.2:p.Arg513Ter	nonsense
NC_000008.11:g.98140831C>T
NC_000008.10:g.99153059C>T
NG_052869.1:g.28539C>T

... more HGVS ... less HGVS

Protein change

R513*

Other names

p.Arg513Ter

Canonical SPDI

NC_000008.11:98140830:C:T

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

protein truncation; Variation Ontology [ VariO:0015]

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00016

Exome Aggregation Consortium (ExAC) 0.00017

The Genome Aggregation Database (gnomAD), exomes 0.00019

The Genome Aggregation Database (gnomAD) 0.00021

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Links

dbSNP: rs149102421 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.
POP1		-	-	GRCh38 GRCh37	356	394

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.
Anauxetic dysplasia 2	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Dec 30, 2021	RCV001330594.7
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 5, 2023	RCV002546397.5
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Nov 15, 2022	RCV004035697.1

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.
Pathogenic (Dec 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anauxetic dysplasia 2 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522320.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Dec 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anauxetic dysplasia 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002569375.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: A heterozygous nonsense variation in exon 11 of the POP1 gene that results in a stop codon and premature truncation of the protein at codon … (more) A heterozygous nonsense variation in exon 11 of the POP1 gene that results in a stop codon and premature truncation of the protein at codon 513 was detected. The observed variant c.1537C>T (p.Arg513Ter) has previously been reported in patient with anauxetic dysplasia. This variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.02% in the gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. (less) Clinical Features: Partial congenital absence of teeth (present) , Abnormal midface morphology (present) Ethnicity/Population group: Hindu Geographic origin: India Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Likely pathogenic (Mar 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anauxetic dysplasia 2 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024729.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Sep 20, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003842601.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 34426522, 28067412, 21455487, 29691392) (less)
Pathogenic (Oct 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003282533.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 21455487 Comment: This sequence change creates a premature translational stop signal (p.Arg513) in the POP1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg513) in the POP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POP1 are known to be pathogenic (PMID: 21455487). This variant is present in population databases (rs149102421, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of anauxetic dysplasia (PMID: 21455487). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1029341). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 15, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005008755.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 21455487‚ 21534943‚ 28067412 Comment: The c.1537C>T (p.R513) alteration, located in exon 11 (coding exon 10) of the POP1 gene, consists of a C to T substitution at nucleotide position … (more) The c.1537C>T (p.R513) alteration, located in exon 11 (coding exon 10) of the POP1 gene, consists of a C to T substitution at nucleotide position 1537. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 513. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported in trans with a second POP1 variant in two siblings with anauxetic dysplasia (Glazov, 2011). Based on the available evidence, this alteration is classified as pathogenic. (less)

Comment:

A heterozygous nonsense variation in exon 11 of the POP1 gene that results in a stop codon and premature truncation of the protein at codon 513 was detected. The observed variant c.1537C>T (p.Arg513Ter) has previously been reported in patient with anauxetic dysplasia. This variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.02% in the gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 34426522, 28067412, 21455487, 29691392)

Comment:

This sequence change creates a premature translational stop signal (p.Arg513*) in the POP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POP1 are known to be pathogenic (PMID: 21455487). This variant is present in population databases (rs149102421, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of anauxetic dysplasia (PMID: 21455487). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1029341). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1537C>T (p.R513*) alteration, located in exon 11 (coding exon 10) of the POP1 gene, consists of a C to T substitution at nucleotide position 1537. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 513. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported in trans with a second POP1 variant in two siblings with anauxetic dysplasia (Glazov, 2011). Based on the available evidence, this alteration is classified as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
protein truncation (VariO:0015)			Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002569375.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Broadening the phenotypic spectrum of POP1-skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia.	Barraza-García J	Clinical genetics	2017	PMID: 28067412
'POP'! The mystery of a skeletal dysplasia vanishes thanks to exome sequencing.	Sutton LM	Clinical genetics	2011	PMID: 21534943
Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia.	Glazov EA	PLoS genetics	2011	PMID: 21455487

Text-mined citations for rs149102421 ...

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_001145860.2(POP1):c.1537C>T (p.Arg513Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149102421 ...