Submissions for variant NM_004795.4(KL):c.2571C>A (p.Asn857Lys)

gnomAD frequency: 0.00048  dbSNP: rs140707985

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001111256	SCV001268799	uncertain significance	Tumoral calcinosis, hyperphosphatemic, familial, 3	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	RCV001856479	SCV002221371	uncertain significance	not provided	2024-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 857 of the KL protein (p.Asn857Lys). This variant is present in population databases (rs140707985, 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 KL-related conditions. ClinVar contains an entry for this variant (Variation ID: 881927). 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 KL 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	RCV004032162	SCV003701676	uncertain significance	not specified	2021-08-30	criteria provided, single submitter	clinical testing	The c.2571C>A (p.N857K) alteration is located in exon 4 (coding exon 4) of the KL gene. This alteration results from a C to A substitution at nucleotide position 2571, causing the asparagine (N) at amino acid position 857 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.