Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5
The NM_001377142.1(PLCB4):c.1079A>T(p.Asp360Val) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D360N) has been classified as Pathogenic.
PLCB4 (HGNC:9059): (phospholipase C beta 4) The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals in the retina. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2010]
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr20-9387476-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 64694.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
?
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, PLCB4
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 20-9387477-A-T is Pathogenic according to our data. Variant chr20-9387477-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 64695.Status of the report is no_assertion_criteria_provided, 0 stars.
Loss of catalytic residue at D360 (P = 0.0463);Loss of catalytic residue at D360 (P = 0.0463);Loss of catalytic residue at D360 (P = 0.0463);Loss of catalytic residue at D360 (P = 0.0463);Loss of catalytic residue at D360 (P = 0.0463);