VCV000871488.39 - ClinVar

NM_001127671.2(LIFR):c.756dup (p.Lys253Ter)

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.

(9)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001127671.2(LIFR):c.756dup (p.Lys253Ter)

Variation ID: 871488 Accession: VCV000871488.39

Type and length

Duplication, 1 bp

Location

Cytogenetic: 5p13.1 5: 38510698-38510699 (GRCh38) [ NCBI UCSC ] 5: 38510800-38510801 (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	May 12, 2020	Oct 20, 2024	Apr 9, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001127671.2:c.756dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121143.1:p.Lys253Ter	nonsense
NM_001364297.2:c.756dup	NP_001351226.1:p.Lys253Ter	nonsense
NM_001364298.2:c.756dup	NP_001351227.1:p.Lys253Ter	nonsense
NM_002310.5:c.756dupT
NM_002310.6:c.756dup	NP_002301.1:p.Lys253Ter	nonsense
NC_000005.10:g.38510699dup
NC_000005.9:g.38510801dup
NG_011817.1:g.89707dup

... more HGVS ... less HGVS

Protein change

K253*

Other names

Canonical SPDI

NC_000005.10:38510698:A:AA

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

dbSNP: rs1745753552 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.
LIFR		-	-	GRCh38 GRCh37	1127	1163

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.
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 9, 2023	RCV001091485.31
Stuve-Wiedemann syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 17, 2023	RCV001809981.4
Stüve-Wiedemann syndrome 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 21, 2022	RCV002286811.6

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 (Nov 30, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832361.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
Pathogenic (Jul 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Stüve-Wiedemann syndrome 1 Affected status: yes Allele origin: biparental	Centogene AG - the Rare Disease Company Accession: SCV002059481.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Feb 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Stüve-Wiedemann syndrome 1 Affected status: yes Allele origin: biparental	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002103032.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: PVS1, PS4_moderate, PM2
Pathogenic (Mar 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Stüve-Wiedemann syndrome 1 Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV002577579.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: PVS1, PM2, PP5
Pathogenic (Jun 21, 2022)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Stüve-Wiedemann syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764775.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Pulmonary arterial hypertension (present) , Abnormal limb bone morphology (present)
Pathogenic (Mar 03, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003837468.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 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 disease; Not observed … (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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24477277, 19371797, 25868946, 34958143, 33305909, 14740318) (less)
Pathogenic (Mar 17, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Stuve-Wiedemann syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003922864.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Publications: PubMed (3) PubMed: 24477277‚ 19371797‚ 14740318 Comment: Variant summary: LIFR c.756dupT (p.Lys253X), also referred to as c.756_757insT, results in a premature termination codon, predicted to cause a truncation of the encoded protein … (more) Variant summary: LIFR c.756dupT (p.Lys253X), also referred to as c.756_757insT, results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250744 control chromosomes (gnomAD). c.756dupT has been reported in the literature in multiple homozygous individuals affected with Stuve-Wiedemann Syndrome (e.g. Dangoneau_2004, Corona-Rivera_2009, Buonuomo_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Apr 09, 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: SCV001582994.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 14740318‚ 24477277‚ 25868946 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 871488). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 871488). This premature translational stop signal has been observed in individuals with Stuve-Wiedemann syndrome (PMID: 14740318, 24477277, 25868946). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys253*) in the LIFR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LIFR are known to be pathogenic (PMID: 14740318). (less)
Pathogenic (Nov 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247559.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24477277, 19371797, 25868946, 34958143, 33305909, 14740318)

Comment:

Variant summary: LIFR c.756dupT (p.Lys253X), also referred to as c.756_757insT, results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250744 control chromosomes (gnomAD). c.756dupT has been reported in the literature in multiple homozygous individuals affected with Stuve-Wiedemann Syndrome (e.g. Dangoneau_2004, Corona-Rivera_2009, Buonuomo_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 871488). This premature translational stop signal has been observed in individuals with Stuve-Wiedemann syndrome (PMID: 14740318, 24477277, 25868946). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys253*) in the LIFR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LIFR are known to be pathogenic (PMID: 14740318).

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

Title	Author	Journal	Year	Link
Stüve-Wiedemann syndrome in a neonate.	Sarafidis K	Pediatrics international : official journal of the Japan Pediatric Society	2015	PMID: 25868946
Long-term follow-up in Stuve-Wiedemann syndrome: a case report with articular involvement.	Buonuomo PS	Clinical dysmorphology	2014	PMID: 24477277
Abnormal oral-pharyngeal swallowing as cause of morbidity and early death in Stüve-Wiedemann syndrome.	Corona-Rivera JR	European journal of medical genetics	2009	PMID: 19371797
Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.	Dagoneau N	American journal of human genetics	2004	PMID: 14740318

Text-mined citations for rs1745753552 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001127671.2(LIFR):c.756dup (p.Lys253Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1745753552 ...