Submissions for variant NM_001127671.2(LIFR):c.247A>G (p.Ile83Val)

gnomAD frequency: 0.00068  dbSNP: rs61751710

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000392680	SCV000457601	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000392680	SCV001472950	uncertain significance	Stuve-Wiedemann syndrome	2019-12-10	criteria provided, single submitter	clinical testing	The LIFR c.247A>G; p.Ile83Val variant (rs61751710), to our knowledge, is not described in the medical literature or in gene-specific databases. It is listed as a variant of uncertain significance in ClinVar (Variation ID: 353633), and is observed in the general population at an overall frequency of 0.047% (114/242,864 alleles) in the Genome Aggregation Database. The isoleucine at codon 83 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty.
GeneDx	RCV001764318	SCV002008426	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278612	SCV002566896	uncertain significance	Connective tissue disorder	2019-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV001764318	SCV003273733	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 83 of the LIFR protein (p.Ile83Val). This variant is present in population databases (rs61751710, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LIFR-related conditions. ClinVar contains an entry for this variant (Variation ID: 353633). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002523524	SCV003658071	uncertain significance	Inborn genetic diseases	2022-06-30	criteria provided, single submitter	clinical testing	The c.247A>G (p.I83V) alteration is located in exon 3 (coding exon 2) of the LIFR gene. This alteration results from a A to G substitution at nucleotide position 247, causing the isoleucine (I) at amino acid position 83 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.