ClinVar Miner

Submissions for variant NM_002977.3(SCN9A):c.1619G>A (p.Arg540His) (rs199748300)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493503 SCV000583077 uncertain significance not provided 2017-05-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN9A gene. The R540H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R540H variant is observed in 14/9238 (0.2%) alleles from individuals of Latino background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R540H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000352094 SCV000418679 likely benign Generalized epilepsy with febrile seizures plus 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000401490 SCV000418680 likely benign Paroxysmal extreme pain disorder 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000293514 SCV000418681 likely benign Small fiber neuropathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000346132 SCV000418682 likely benign Inherited Erythromelalgia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000399515 SCV000418683 likely benign Familial Febrile Seizures 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000306480 SCV000418684 likely benign Severe myoclonic epilepsy in infancy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000363472 SCV000418685 likely benign Congenital Indifference to Pain 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000688718 SCV000816341 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2018-06-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 540 of the SCN9A protein (p.Arg540His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199748300, ExAC 0.2%). This variant has not been reported in the literature in individuals with SCN9A-related disease. ClinVar contains an entry for this variant (Variation ID: 331988). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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