rs104895462

Positions:

• chr16-50710911-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001370466.1(NOD2):​c.919C>T​(p.Arg307Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 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. R307Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.06

Genes affected

NOD2 (HGNC:5331): (nucleotide binding oligomerization domain containing 2) This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-50710912-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 16-50710911-C-T is Pathogenic according to our data. Variant chr16-50710911-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50710911-C-T is described in Lovd as [Pathogenic]. Variant chr16-50710911-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.919C>T	p.Arg307Trp	missense_variant	4/12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.919C>T	p.Arg307Trp	missense_variant	4/12		NM_001370466.1	ENSP00000495993	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Blau syndrome Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The observed missense c.919C>Tp.Arg307Trp variant in NOD2 gene has been reported previously in heterozygous state in multiple individuals affected with Blau syndrome Rosé CD, et al., 2015; Ikeda K, et al., 2014; Xiang H, et al., 2012; Milman N, et al., 2006. This variant has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects NOD2 function Tanabe T, et al., 2004. The p.Arg307Trp variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic multiple submissions. Multiple lines of computational evidences Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this posiiton on NOD2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 307 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.1000C>T in Exon 4 of the NOD2 gene that results in the amino acid substitution p.Arg334Trp was identified. The observed variantis novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 4696] The observed variation has previously been reported for Blau syndrome by Janarthanan, Mahesh, et al., 2019. Experimental studies have shown that this missense change affects NOD2 function by Tanabe, Tsuyoshi, et al., 2004. For these reasons this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	NOD2: PM2, PM5, PM6, PP1:Moderate, PP4, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2022	Published functional studies demonstrate a gain of function effect resulting in hyperactivation of the receptor (Parkhouse et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32597225, 32881073, 32647028, 14522785, 17069729, 20199415, 22509093, 17916199, 28721627, 32707200, 17157607, 32346654, 31543536, 33923123, 34093558, 22377804, 24713464, 25429073, 31120540, 17372104, 30574935, 25416713, 11528384, 25093298) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 20, 2022	PP1_strong, PM2_supporting, PM5, PM6_strong, PS3, PS4 -

Regional enteritis;C5201146:Blau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the NOD2 protein (p.Arg334Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Blau syndrome (PMID: 11528384, 14522785, 15459013, 17157607, 17207093, 20199415, 22509093, 24713464, 25416713). 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. ClinVar contains an entry for this variant (Variation ID: 4696). 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. Experimental studies have shown that this missense change affects NOD2 function (PMID: 15044951, 15459013). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.5	.;H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.8	.;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.95		.;Gain of catalytic residue at C338 (P = 0.0863);
MVP		0.92
MPC		0.51
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.74
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104895462; hg19: chr16-50744822;