ClinVar Genomic variation as it relates to human health

The heterozygous p.Asp630Asn variant was identified by our study in one individual with auriculocondylar syndrome. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. The Aspartic Acid (Asp) at position 630 is conserved in mammals and evolutionarily distant species, raising supporting that a change at this position may not be tolerated. Computational prediction tools do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (PMID: 33258288, 31395954 PS1_P). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asp642Tyr) has been reported as pathogenic (PMID: 31186267, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.832, PP3). Therefore, this variant is classified as likley pathogenic according to the recommendation of ACMG/AMP guideline.

This variant has been previously reported as a heterozygous change, of unknown inheritance, in a deceased infant, as a de novo heterozygous change in an individual included in a large cohort with unspecified rare disease, and as a de novo change in a preterm infant with congenital syngnathism, severe migrognathia and a concern for ear anomaly (PMID: 33258288, 31395954, 32826208). This variant has also been identified in tumor samples of blue nevus-like melanoma and uveal melanoma (PMID: 31357599, 26683228, 27089179, 28409567). The PLCB4 gene is constrained against missense variation (Z score=3.57). The c.1888G>A (p.Asp630Asn) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1888G>A (p.Asp630Asn) variant affects a highly conserved amino acid; however, in silico analyses predict a discordant effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1888G>A (p.Asp630Asn) variant is classified as Likely Pathogenic.

Reported as a heterozygous variant in an infant with a postmortem diagnosis of auriculocondylar syndrome; detailed clinical information was not provided (PMID: 31395954); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28409567, 27089179, 26683228, 31357599, 33258288, 31395954)