rs587777247
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001288705.3(CSF1R):c.2342C>T(p.Ala781Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 AF: 6.84e-7 AC: 1AN: 1461892Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse leukoencephalopathy with spheroids Pathogenic:1Other:1
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This variant has been previously reported as disease-causing and was found once in our laboratory in a 42-year-old female with progressive neurologic decline, upper motor neuron pathology, and diffuse demyelinating lesions in the brain. Father was similarly affected (not tested). -
not provided Pathogenic:1
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 781 of the CSF1R protein (p.Ala781Val). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala781 amino acid residue in CSF1R. Other variant(s) that disrupt this residue have been observed in individuals with CSF1R-related conditions (PMID: 24336230), which suggests that this may be a clinically significant amino acid residue. 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 CSF1R protein function. ClinVar contains an entry for this variant (Variation ID: 162118). This missense change has been observed in individuals with clinical features of hereditary diffuse leukoencephalopathy with spheroids (PMID: 23816250, 24198292, 25563800; Invitae). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at