NM_001330078.2(NRXN1):c.2533C>T (p.His845Tyr) AND Pitt-Hopkins-like syndrome 2

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 22, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000465496.29

Allele description [Variation Report for NM_001330078.2(NRXN1):c.2533C>T (p.His845Tyr)]

NM_001330078.2(NRXN1):c.2533C>T (p.His845Tyr)

Gene:

NRXN1:neurexin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_001330078.2(NRXN1):c.2533C>T (p.His845Tyr)

Other names:

p.H885Y:CAT>TAT; p.His885Tyr

HGVS:

NC_000002.12:g.50497679G>A
NG_011878.1:g.539858C>T
NM_001135659.3:c.2653C>T
NM_001330077.2:c.2509C>T
NM_001330078.2:c.2533C>TMANE SELECT
NM_001330082.2:c.2509C>T
NM_001330083.2:c.2467C>T
NM_001330084.2:c.2467C>T
NM_001330085.2:c.2506C>T
NM_001330086.2:c.2533C>T
NM_001330087.2:c.2422C>T
NM_001330088.2:c.2452C>T
NM_001330093.2:c.2530C>T
NM_001330094.2:c.2521C>T
NM_001330095.2:c.2482C>T
NM_001330096.2:c.2422C>T
NM_004801.6:c.2533C>T
NP_001129131.1:p.His885Tyr
NP_001317006.1:p.His837Tyr
NP_001317007.1:p.His845Tyr
NP_001317011.1:p.His837Tyr
NP_001317012.1:p.His823Tyr
NP_001317013.1:p.His823Tyr
NP_001317014.1:p.His836Tyr
NP_001317015.1:p.His845Tyr
NP_001317016.1:p.His808Tyr
NP_001317017.1:p.His818Tyr
NP_001317022.1:p.His844Tyr
NP_001317023.1:p.His841Tyr
NP_001317024.1:p.His828Tyr
NP_001317025.1:p.His808Tyr
NP_004792.1:p.His845Tyr
NC_000002.11:g.50724817G>A
NM_001135659.1:c.2653C>T
NM_001135659.2:c.2653C>T

Protein change:

H808Y

Links:

dbSNP: rs199784139

NCBI 1000 Genomes Browser:

rs199784139

Molecular consequence:

NM_001135659.3:c.2653C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330077.2:c.2509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330078.2:c.2533C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330082.2:c.2509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330083.2:c.2467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330084.2:c.2467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330085.2:c.2506C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330086.2:c.2533C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330087.2:c.2422C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330088.2:c.2452C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330093.2:c.2530C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330094.2:c.2521C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330095.2:c.2482C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330096.2:c.2422C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004801.6:c.2533C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Pitt-Hopkins-like syndrome 2 (PTHSL2)
Identifiers:: MONDO: MONDO:0013690; MedGen: C3280479; Orphanet: 221150; OMIM: 614325

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000552204	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 22, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001302024	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001529580	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 28, 2018)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003814163	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 11, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.

Jiang YH, Yuen RK, Jin X, Wang M, Chen N, Wu X, Ju J, Mei J, Shi Y, He M, Wang G, Liang J, Wang Z, Cao D, Carter MT, Chrysler C, Drmic IE, Howe JL, Lau L, Marshall CR, Merico D, Nalpathamkalam T, et al.

Am J Hum Genet. 2013 Aug 8;93(2):249-63. doi: 10.1016/j.ajhg.2013.06.012. Epub 2013 Jul 11.

PubMed [citation]

PMID:: 23849776
PMCID:: PMC3738824

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000552204.10

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

#	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

From Illumina Laboratory Services, Illumina, SCV001302024.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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

From Baylor Genetics, SCV001529580.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Revvity Omics, Revvity, SCV003814163.2

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

#	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: May 19, 2024

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