Submissions for variant NM_199242.3(UNC13D):c.3151G>A (p.Gly1051Arg)

dbSNP: rs1232542382

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001310042	SCV001499564	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1051 of the UNC13D protein (p.Gly1051Arg). This variant also falls at the last nucleotide of exon 31, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 34339548). ClinVar contains an entry for this variant (Variation ID: 1012139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002264261	SCV002543181	uncertain significance	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526107	SCV005039335	pathogenic	Familial hemophagocytic lymphohistiocytosis	2024-03-13	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.3151G>A (p.Gly1051Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.3151G>A has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis. These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 1012139). Based on the evidence outlined above, the variant was classified as pathogenic.