NM_000751.3(CHRND):c.1480T>C (p.Tyr494His) AND Lethal multiple pterygium syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 3, 2023
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:: RCV000803667.7

Allele description [Variation Report for NM_000751.3(CHRND):c.1480T>C (p.Tyr494His)]

NM_000751.3(CHRND):c.1480T>C (p.Tyr494His)

Gene:

CHRND:cholinergic receptor nicotinic delta subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q37.1

Genomic location:

Preferred name:

NM_000751.3(CHRND):c.1480T>C (p.Tyr494His)

HGVS:

NC_000002.12:g.232535238T>C
NG_008028.1:g.14027T>C
NG_012954.2:g.547T>C
NM_000751.3:c.1480T>CMANE SELECT
NM_001256657.2:c.1435T>C
NM_001311195.2:c.898T>C
NM_001311196.2:c.1177T>C
NP_000742.1:p.Tyr494His
NP_001243586.1:p.Tyr479His
NP_001298124.1:p.Tyr300His
NP_001298125.1:p.Tyr393His
LRG_1275:g.547T>C
NC_000002.11:g.233399948T>C
NM_000751.2:c.1480T>C

Protein change:

Y300H

Links:

dbSNP: rs368695808

NCBI 1000 Genomes Browser:

rs368695808

Molecular consequence:

NM_000751.3:c.1480T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001256657.2:c.1435T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001311195.2:c.898T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001311196.2:c.1177T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lethal multiple pterygium syndrome (LMPS)
Identifiers:: MONDO: MONDO:0009668; MedGen: C1854678; Orphanet: 33108; OMIM: 253290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000943549	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Nov 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002318805	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000943549

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Nov 3, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002318805

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 22, 2022)

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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000943549.4

#	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 3billion, SCV002318805.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000634). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.795>=0.6). A missense variant is a common mechanism . Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Sep 29, 2024

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