Submissions for variant NM_001288705.3(CSF1R):c.2768A>G (p.Tyr923Cys)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences	RCV003334444	SCV004042651	likely pathogenic	Leukoencephalopathy, diffuse hereditary, with spheroids 1	2023-10-05	criteria provided, single submitter	clinical testing	A novel missense variant of uncertain significance NM_005211.4:c.2768A>G in CSF1R gene was identified in heterozygous state in the proband. The NP_005202.2:p.Tyr923Cys variant is novel (not in any individuals) in 1000 Genomes, in gnomAD as well as in our inhouse database. There is a large physicochemical difference between tyrosine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.Tyr923Cys missense variant is predicted to be damaging by both SIFT and PolyPhen2. The gene CSF1R has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.57. The gene CSF1R contains 28 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. In addition, the clinical phenotype of the proband especially the MRI matches completely with that of the disorder caused by pathogenic variants in CSF1R gene. For these reasons, this variant has been classified as Likely Pathogenic (PM2 PP2 PP3 PP4_Moderate).