Submissions for variant NM_198525.3(KIF7):c.461G>A (p.Arg154Gln)

gnomAD frequency: 0.00053  dbSNP: rs180758272

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000547008	SCV000636835	uncertain significance	Acrocallosal syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 154 of the KIF7 protein (p.Arg154Gln). This variant is present in population databases (rs180758272, gnomAD 0.2%). This missense change has been observed in individual(s) with acrocallosal syndrome (PMID: 26174511). ClinVar contains an entry for this variant (Variation ID: 463144). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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.
Eurofins Ntd Llc (ga)	RCV000733768	SCV000861865	uncertain significance	not provided	2018-06-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001249725	SCV001423751	uncertain significance	KIF7-related ciliopathy spectrum disorder	2019-10-29	criteria provided, single submitter	clinical testing	The KIF7 c.461G>A (p.Arg154Gln) missense variant has been reported in one study in which it is identified in a heterozygous state of unknown inheritance in one individual with KIF7-related ciliopathy spectrum disorder. The affected individual also carried a second missense variant in the KIF7 gene in a heterozygous state, which was shown to be maternally inherited. Paternal DNA was not available for testing (Tunovic et al. 2015). The p.Arg154Gln variant is reported at a frequency of 0.001560 in the African population of the Genome Aggregation Database in a region of good sequence coverage. The Arg154 residue is located in the kinesin motor domain. Based on the limited evidence, the p.Arg154Gln variant is classified as a variant of unknown significance for KIF7-related ciliopathy spectrum disorder.
GeneDx	RCV000733768	SCV001776395	uncertain significance	not provided	2020-09-15	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state with a second KIF7 variant in an individual with features of acrocallosal syndrome (Tunovic et al., 2015).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 25131622, 26174511)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000733768	SCV004013278	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	PM2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000733768	SCV001549079	uncertain significance	not provided		no assertion criteria provided	clinical testing	The KIF7 p.Arg154Gln variant was identified in two individuals with neurodevelopmental features similar to acrocallosal syndrome (Tunovic_2015_PMID:26174511; Srivastava_2014_PMID:25131622). These individuals were compound heterozygous for the KIF7 p.Arg154Gln variant and either p.Glu987Lys or p.E987K. The variant was identified in dbSNP (ID: rs180758272) and ClinVar (classified as uncertain significance by Invitae and EGL Genetic Diagnostics). The variant was identified in control databases in 31 of 188318 chromosomes at a frequency of 0.0001646 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 26 of 16664 chromosomes (freq: 0.00156), Latino in 3 of 25532 chromosomes (freq: 0.000118) and European (non-Finnish) in 2 of 76266 chromosomes (freq: 0.000026), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Arg154 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.