ClinVar Miner

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

dbSNP: rs1232542382
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp 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 canonical 5' splicing donor site and two predict the variant weakens this site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Xinh_2021), resulting in exon 31 skipping. The frequency data for this variant in gnomAD v2.1 is considered unreliable, as metrics indicate poor data quality at this position, however it was found at a frequency of 2.16e-6 in gnomAD v.4.0. c.3151G>A has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (Xinh_2021). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 34339548). ClinVar contains an entry for this variant (Variation ID: 1012139). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001310042 SCV005651920 pathogenic Familial hemophagocytic lymphohistiocytosis 3 2024-03-14 criteria provided, single submitter clinical testing

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