Submissions for variant NM_198525.3(KIF7):c.3871G>A (p.Glu1291Lys)

gnomAD frequency: 0.00008  dbSNP: rs751191936

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001116732	SCV001274857	uncertain significance	Acrocallosal syndrome	2018-01-12	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	RCV001116732	SCV001416382	uncertain significance	Acrocallosal syndrome	2022-10-17	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 1291 of the KIF7 protein (p.Glu1291Lys). This variant is present in population databases (rs751191936, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with KIF7-related conditions. ClinVar contains an entry for this variant (Variation ID: 885251). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF7 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.
GeneDx	RCV001593279	SCV001816285	uncertain significance	not provided	2022-09-24	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
Revvity Omics, Revvity	RCV001593279	SCV003810055	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001593279	SCV005193989	uncertain significance	not provided		criteria provided, single submitter	not provided
Ambry Genetics	RCV004986820	SCV005611558	uncertain significance	Inborn genetic diseases	2024-07-31	criteria provided, single submitter	clinical testing	The c.3871G>A (p.E1291K) alteration is located in exon 19 (coding exon 18) of the KIF7 gene. This alteration results from a G to A substitution at nucleotide position 3871, causing the glutamic acid (E) at amino acid position 1291 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.