chr5-150056331-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001288705.3(CSF1R):c.2330G>A(p.Arg777Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001288705.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 777 of the CSF1R protein (p.Arg777Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hereditary diffuse leukoencephalopathy with spheroids (PMID: 23649896, 24198292). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162111). 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) has been performed 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 CSF1R protein function. This variant disrupts the p.Arg777 amino acid residue in CSF1R. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23038421, 23649896, 30268725). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate a damaging effect (PMID: 34652888); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27338940, 24198292, 24034409, 32430064, 30614382, 34541732, 36683899, 23649896, 35713703, 30115677, 24428556, 34652888) -
CSF1R-related disorder Pathogenic:1
The CSF1R c.2330G>A variant is predicted to result in the amino acid substitution p.Arg777Gln. This variant has been reported to be causative for autosomal dominant diffuse hereditary leukoencephalopathy with spheroids (Guerreiro et al. 2013. PubMed ID: 23649896; Karle et al. 2013. PubMed ID: 24198292; Codjia et al. 2018. PubMed ID: 30115677; Makary et al. 2019. PubMed ID: 30614382; Kempthorne et al. 2020. PubMed ID: 32430064). Of note, a different missense variant affecting the same residue (p.Arg777Trp) has also been reported to be pathogenic for diffuse hereditary leukoencephalopathy with spheroids (Guerreiro et al. 2013. PubMed ID: 23649896). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -
Leukoencephalopathy, diffuse hereditary, with spheroids 1 Pathogenic:1
Criteria applied: PS4,PM1,PM2,PM5,PP3 -
Hereditary diffuse leukoencephalopathy with spheroids Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at