rs104895461
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001370466.1(NOD2):c.920G>A(p.Arg307Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307W) has been classified as Pathogenic.
Frequency
Consequence
NM_001370466.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOD2 | NM_001370466.1 | c.920G>A | p.Arg307Gln | missense_variant | 4/12 | ENST00000647318.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOD2 | ENST00000647318.2 | c.920G>A | p.Arg307Gln | missense_variant | 4/12 | NM_001370466.1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461862Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1AN XY: 727232
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2015 | The R334Q variant in the NOD2 gene has been reported previously in multiple individuals diagnosed withBlau syndrome as well as expanded features including lymphadenopathy, interstitial lung disease, hepaticgranuloma, granulomatous arthritis, erythema nodosum, hypertension and recurrent fever (Rosé et al.,2015; Akil et al., 2010; Becker et al., 2007; Miceli-Richard et al., 2001). The R334Q substitution was notobserved in approximately 6500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The R334Qvariant is a semi-conservative amino acid substitution, which may impact secondary protein structure asthese residues differ in some properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function. Weinterpret R334Q as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
Blau syndrome Pathogenic:1Other:1
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2001 | - - |
Regional enteritis;C5201146:Blau syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | Experimental studies have shown that this missense change affects NOD2 function (PMID: 12626759, 15044951, 25093298, 25429073). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOD2 protein function. ClinVar contains an entry for this variant (Variation ID: 4694). This missense change has been observed in individual(s) with Blau syndrome (PMID: 11528384, 15554080, 17393391, 20084402, 24713464, 26606664). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 334 of the NOD2 protein (p.Arg334Gln). This variant disrupts the p.Arg334 amino acid residue in NOD2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11528384, 14522785, 15044951, 15459013, 17157607, 17207093, 20199415, 22509093, 24713464, 25416713). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at