ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.1115G>A (p.Arg372His) (rs201071819)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000757743 SCV000292972 uncertain significance not provided 2015-07-20 criteria provided, single submitter clinical testing The R372H variant in the SCN9A gene has not been published as a pathogenic, nor has it been reported as a benign polymorphism to our knowledge. The R327H variant was not observed at any significant frequency in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position within the first of four repeats between helical transmembrane domains 5 and 6, that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R372H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.We interpret R372H as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757743 SCV000886083 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing The p.Arg372His variant (rs201071819) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.08 percent in the Ashkenazi Jewish population (identified on 8 out of 9,466 chromosomes) and has been reported to the ClinVar database as uncertain significance (Variation ID: 245825). The arginine at position 372 is highly conserved up to platypus considering 12 species (Alamut v2.11) and computational analyses of the p.Arg372His variant on protein structure and function indicate a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Arg372His variant with certainty.
Invitae RCV000801396 SCV000941170 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2020-05-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 372 of the SCN9A protein (p.Arg372His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201071819, ExAC 0.01%). This variant has not been reported in the literature in individuals with SCN9A-related disease. ClinVar contains an entry for this variant (Variation ID: 245825). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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