Submissions for variant NM_001288705.3(CSF1R):c.2746G>A (p.Glu916Lys)

gnomAD frequency: 0.00033  dbSNP: rs142435467

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000513367	SCV000609186	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CSF1R: BP4
Illumina Laboratory Services, Illumina	RCV001157186	SCV001318736	benign	Hereditary diffuse leukoencephalopathy with spheroids	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000513367	SCV001999638	uncertain significance	not provided	2020-01-09	criteria provided, single submitter	clinical testing	Identified in two Caucasian elderly control individuals in a study on adult-onset leukodystrophy genes in Alzheimer's disease (Sassi et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29544907)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000513367	SCV002404508	benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002524968	SCV003613705	uncertain significance	Inborn genetic diseases	2021-12-10	criteria provided, single submitter	clinical testing	The c.2746G>A (p.E916K) alteration is located in exon 21 (coding exon 20) of the CSF1R gene. This alteration results from a G to A substitution at nucleotide position 2746, causing the glutamic acid (E) at amino acid position 916 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000513367	SCV001552186	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CSF1R p.Glu916Lys variant was not identified in the literature but was identified in dbSNP (ID: rs142435467), ClinVar (classified as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen) and LOVD 3.0 (classified as likely benign by VKGL data sharing initiative Nederland). The variant was identified in control databases in 91 of 282020 chromosomes at a frequency of 0.0003227 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 86 of 128448 chromosomes (freq: 0.00067), Other in 1 of 7212 chromosomes (freq: 0.000139), Latino in 3 of 35412 chromosomes (freq: 0.000085) and South Asian in 1 of 30608 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Glu916 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000513367	SCV001808407	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513367	SCV001974475	likely benign	not provided		no assertion criteria provided	clinical testing