Submissions for variant NM_006563.5(KLF1):c.478G>A (p.Glu160Lys)

gnomAD frequency: 0.00060  dbSNP: rs772655521

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000290356	SCV000410852	uncertain significance	Congenital dyserythropoietic anemia type 4	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002521193	SCV003251060	uncertain significance	not provided	2024-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 160 of the KLF1 protein (p.Glu160Lys). This variant is present in population databases (rs772655521, gnomAD 0.2%), 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 KLF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 328318). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KLF1 protein function with a negative predictive value of 80%. 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	RCV002523053	SCV003581420	uncertain significance	Inborn genetic diseases	2024-04-23	criteria provided, single submitter	clinical testing	The c.478G>A (p.E160K) alteration is located in exon 2 (coding exon 2) of the KLF1 gene. This alteration results from a G to A substitution at nucleotide position 478, causing the glutamic acid (E) at amino acid position 160 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV002521193	SCV005192612	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003957677	SCV004778971	likely benign	KLF1-related disorder	2022-08-03	no assertion criteria provided	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).