NM_001370466.1(NOD2):c.1459T>C (p.Tyr487His) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 16, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000520892.14

Allele description [Variation Report for NM_001370466.1(NOD2):c.1459T>C (p.Tyr487His)]

NM_001370466.1(NOD2):c.1459T>C (p.Tyr487His)

Gene:

NOD2:nucleotide binding oligomerization domain containing 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q12.1

Genomic location:

Preferred name:

NM_001370466.1(NOD2):c.1459T>C (p.Tyr487His)

HGVS:

NC_000016.10:g.50711451T>C
NG_007508.1:g.19313T>C
NM_001293557.2:c.1459T>C
NM_001370466.1:c.1459T>CMANE SELECT
NM_022162.3:c.1540T>C
NP_001280486.1:p.Tyr487His
NP_001357395.1:p.Tyr487His
NP_071445.1:p.Tyr514His
LRG_177t1:c.1540T>C
LRG_177:g.19313T>C
NC_000016.9:g.50745362T>C
NM_022162.1:c.1540T>C
NM_022162.2:c.1540T>C
NR_163434.1:n.1524T>C

Protein change:

Y487H

Links:

dbSNP: rs540122692

NCBI 1000 Genomes Browser:

rs540122692

Molecular consequence:

NM_001293557.2:c.1459T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370466.1:c.1459T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_022162.3:c.1540T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_163434.1:n.1524T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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protein ABIL1 isoform X1 [Ricinus communis]
protein ABIL1 isoform X1 [Ricinus communis]
gi|1000982894|ref|XP_015584586.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617946	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 7, 2015)	germline	clinical testing	Citation Link,
SCV001477864	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Feb 16, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617946

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Dec 7, 2015)

germline

clinical testing

Citation Link,

SCV001477864

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Feb 16, 2020)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000617946.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The Y514H variant in the NOD2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y514H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y514H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D512H, M513T, M513R) have been reported in the Human Gene Mutation Database in association with NOD2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret Y514H as a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001477864.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The NOD2 c.1540T>C; p.Tyr514His variant (rs540122692) is described in the literature in one individual with suspected Yao syndrome (Yang 2018). The variant is reported as a variant of uncertain significance in the ClinVar database (Variation ID: 449632) and in the general population with an overall allele frequency of 0.004% (11/250,384 alleles) in the Genome Aggregation Database. The tyrosine at codon 514 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Tyr514His variant is uncertain at this time. References: Yang et al. A Chinese case series of Yao syndrome and literature review. Clin Rheumatol. 2018 Dec;37(12):3449-3454.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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