NM_000751.3(CHRND):c.1334T>C (p.Ile445Thr) AND Lethal multiple pterygium syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001225459.7

Allele description [Variation Report for NM_000751.3(CHRND):c.1334T>C (p.Ile445Thr)]

NM_000751.3(CHRND):c.1334T>C (p.Ile445Thr)

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.1334T>C (p.Ile445Thr)

Other names:

NM_001311196.2:c.1031T>C

HGVS:

NC_000002.12:g.232534305T>C
NG_008028.1:g.13094T>C
NM_000751.3:c.1334T>CMANE SELECT
NM_001256657.2:c.1289T>C
NM_001311195.2:c.752T>C
NM_001311196.2:c.1031T>C
NP_000742.1:p.Ile445Thr
NP_001243586.1:p.Ile430Thr
NP_001298124.1:p.Ile251Thr
NP_001298125.1:p.Ile344Thr
NC_000002.11:g.233399015T>C
NC_000002.11:g.233399015T>C
NM_000751.2:c.1334T>C

Protein change:

I251T

Links:

dbSNP: rs573680102

NCBI 1000 Genomes Browser:

rs573680102

Molecular consequence:

NM_000751.3:c.1334T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001256657.2:c.1289T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001311195.2:c.752T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001311196.2:c.1031T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001397740	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23108489, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001397740

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 23, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Pregnancy in congenital myasthenic syndrome.

Servais L, Baudoin H, Zehrouni K, Richard P, Sternberg D, Fournier E, Eymard B, Stojkovic T.

J Neurol. 2013 Mar;260(3):815-9. doi: 10.1007/s00415-012-6709-x. Epub 2012 Oct 30.

PubMed [citation]

PMID:: 23108489

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001397740.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt CHRND protein function. ClinVar contains an entry for this variant (Variation ID: 953201). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 23108489). This variant is present in population databases (rs573680102, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 445 of the CHRND protein (p.Ile445Thr).

#	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 8, 2024

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