ClinVar Genomic variation as it relates to human health

NLRC4: BS1

Variant summary: NLRC4 c.928C>T (p.Arg310X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however the molecular mechanism of disease attributed to NLRC4 is gain-of-function. The variant allele was found at a frequency of 0.00017 in 251260 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NLRC4 causing NLRC4-Related Disorders, allowing no conclusion about variant significance. c.928C>T has been reported in the literature in heterozygous individuals affected with clinical features of NLRC4-Related Disorders (e.g., Popplewell_2020, Karacan_2019), however, these report(s) do not provide unequivocal conclusions about association of the variant with NLRC4-Related Disorders. c.928C>T has also been identified in unaffected relatives of affected individuals with the variant (Popplewell_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30783801, 32529290). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified it as a variant of uncertain significance, while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

ACMG: none

This sequence change creates a premature translational stop signal (p.Arg310*) in the NLRC4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NLRC4 cause disease. This variant is present in population databases (rs199475953, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with systemic autoinflammatory disease (PMID: 30783801). ClinVar contains an entry for this variant (Variation ID: 103085). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The NLRC4 p.R310* variant was identified in 1 of 392 proband chromosomes (frequency: 0.00255) from individuals with systemic autoinflammatory diseases (Karacan_2019_PMID:30783801). The variant was also reported in another case study in a female child with an auto-inflammatory syndrome phenotype (Sleptsova_2016). The variant was identified in dbSNP (ID: rs199475953) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 48 of 282654 chromosomes at a frequency of 0.0001698 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 40 of 129004 chromosomes (freq: 0.00031), Latino in 5 of 35434 chromosomes (freq: 0.000141), Other in 1 of 7224 chromosomes (freq: 0.000138) and European (Finnish) in 2 of 25110 chromosomes (freq: 0.00008), but was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. The c.928C>T variant leads to a premature stop codon at position 310 which is predicted to lead to a truncated or absent protein and loss of function. The role of NLRC4 loss of function variants in disease is currently not well established. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Converted during submission to not provided.