rs201354321
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001365536.1(SCN9A):c.1604C>T(p.Ser535Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000344 in 1,600,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S535A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001365536.1 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN9A | NM_001365536.1 | c.1604C>T | p.Ser535Leu | missense_variant, splice_region_variant | 12/27 | ENST00000642356.2 | |
SCN1A-AS1 | NR_110260.1 | n.1029+7576G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.1604C>T | p.Ser535Leu | missense_variant, splice_region_variant | 12/27 | NM_001365536.1 | P1 | ||
SCN1A-AS1 | ENST00000651574.1 | n.1707+7576G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000129 AC: 3AN: 232786Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 126788
GnomAD4 exome AF: 0.0000345 AC: 50AN: 1448406Hom.: 0 Cov.: 32 AF XY: 0.0000347 AC XY: 25AN XY: 720096
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74306
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 26, 2017 | The p.Ser535Leu variant (rs201354321) 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 an overall population frequency of 0.002 percent (identified on 4 out of 260,912 chromosomes). The serine at position 535 is highly conserved considering 12 species (Alamut v2.9.0) and computational analyses of the effects of the p.Ser535Leu variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Ser535Leu variant with certainty. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Primary erythromelalgia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Aug 18, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2023 | The c.1604C>T (p.S535L) alteration is located in exon 12 (coding exon 11) of the SCN9A gene. This alteration results from a C to T substitution at nucleotide position 1604, causing the serine (S) at amino acid position 535 to be replaced by a leucine (L). The alteration is ultra rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the SCN9A c.1604C>T alteration was observed in 0.002% (4/264,180) of total alleles studied. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.S535 amino acid is conserved in available vertebrate species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.S535L alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Primary erythromelalgia;C0751122:Severe myoclonic epilepsy in infancy;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive;C2751778:Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 535 of the SCN9A protein (p.Ser535Leu). This variant is present in population databases (rs201354321, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 538480). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at