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

dbSNP: rs1745753552

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001091485	SCV001247559	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001091485	SCV001582994	pathogenic	not provided	2023-04-09	criteria provided, single submitter	clinical testing	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).
Blueprint Genetics	RCV001091485	SCV001832361	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001809981	SCV002059481	pathogenic	Stuve-Wiedemann syndrome	2019-07-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001809981	SCV002103032	pathogenic	Stuve-Wiedemann syndrome	2021-02-10	criteria provided, single submitter	clinical testing	PVS1, PS4_moderate, PM2
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002286811	SCV002577579	pathogenic	Stüve-Wiedemann syndrome 1	2022-03-02	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV002286811	SCV002764775	pathogenic	Stüve-Wiedemann syndrome 1	2022-06-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001091485	SCV003837468	pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001809981	SCV003922864	pathogenic	Stuve-Wiedemann syndrome	2023-03-17	criteria provided, single submitter	clinical testing	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.