Submissions for variant NM_001127671.2(LIFR):c.3288C>A (p.Asn1096Lys)

dbSNP: rs3729751

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000326373	SCV000457571	likely benign	Stuve-Wiedemann syndrome	2018-01-13	criteria provided, single submitter	clinical testing	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000891051	SCV001034840	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000891051	SCV001786006	uncertain significance	not provided	2020-08-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28334964)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003103991	SCV002049446	uncertain significance	Stüve-Wiedemann syndrome 1	2022-04-14	criteria provided, single submitter	clinical testing	The LIFR c.3288C>A; p.Asn1096Lys variant (rs3729751) is reported in the literature in several individuals affected with urinary tract malformations as well as in a healthy parent (Kosfeld 2017), but it has not, to our knowledge, been reported in association with skeletal dysplasia. This variant is reported with discrepant classifications in the ClinVar database (Variation ID: 353605) and is found in the non-Finnish European population with an allele frequency of 0.28% (363/129,018 alleles) in the Genome Aggregation Database. The asparagine at codon 1096 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Functional studies suggest the variant protein is expressed in the cell at wildtype levels but may exhibit slightly diminished cell-surface expression, although it is unclear if this difference is clinically significant (Kosfeld 2017). Due to limited information, the clinical significance of the p.Asn1096Lys variant is uncertain at this time. References: Kosfeld et al. Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations. Hum Mol Genet. 2017 May 1;26(9):1716-1731. PMID: 28334964.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155170	SCV003844901	uncertain significance	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: LIFR c.3288C>A (p.Asn1096Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250856 control chromosomes. The observed variant frequency is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in LIFR causing Stuve-Wiedemann Syndrome phenotype (0.0011), suggesting that the variant may be benign. c.3288C>A has been reported in the literature in individuals affected with congenital anomalies of the kidneys and urinary tract (Kosfeld_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Stuve-Wiedemann Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Kosfeld_2017). ClinVar contains an entry for this variant (Variation ID: 353605). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV000891051	SCV004160932	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	LIFR: BS1
PreventionGenetics, part of Exact Sciences	RCV003902371	SCV004723087	likely benign	LIFR-related condition	2022-05-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Weber Lab, Hannover Medical School	RCV000490985	SCV000346034	uncertain significance	Congenital anomaly of kidney and urinary tract	2024-02-15	no assertion criteria provided	research
Natera, Inc.	RCV000326373	SCV001452982	likely benign	Stuve-Wiedemann syndrome	2020-01-12	no assertion criteria provided	clinical testing