NM_000079.4(CHRNA1):c.2T>C (p.Met1Thr) AND Lethal multiple pterygium syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 31, 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:: RCV001136251.13

Allele description [Variation Report for NM_000079.4(CHRNA1):c.2T>C (p.Met1Thr)]

NM_000079.4(CHRNA1):c.2T>C (p.Met1Thr)

Gene:

CHRNA1:cholinergic receptor nicotinic alpha 1 subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.1

Genomic location:

Preferred name:

NM_000079.4(CHRNA1):c.2T>C (p.Met1Thr)

HGVS:

NC_000002.12:g.174764393A>G
NG_008172.1:g.5080T>C
NM_000079.4:c.2T>CMANE SELECT
NM_001039523.3:c.2T>C
NP_000070.1:p.Met1Thr
NP_001034612.1:p.Met1Thr
NC_000002.11:g.175629121A>G
NM_000079.3:c.2T>C

Protein change:

M1T

Links:

dbSNP: rs779169597

NCBI 1000 Genomes Browser:

rs779169597

Molecular consequence:

NM_000079.4:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001039523.3:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000079.4:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001039523.3:c.2T>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
SCV001296080	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 6, 2018)	germline	clinical testing	Citation Link,
SCV001362282	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 28, 2023)	germline	clinical testing	Citation Link,
SCV001540422	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 31, 2023)	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

SCV001296080

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 6, 2018)

germline

clinical testing

Citation Link,

SCV001362282

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 28, 2023)

germline

clinical testing

Citation Link,

SCV001540422

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 31, 2023)

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

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

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001296080.2

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362282.3

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

Description

Variant summary: CHRNA1 c.2T>C (p.Met1Thr) alters the initiation codon (the next potential start site is located in exon 5) and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Four of four in-silico tools predict a damaging effect of the variant on protein function. Additionally, pathogenic variants have been reported upstream of the next in-frame methionine. The variant allele was found at a frequency of 3.6e-05 in 247776 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2T>C in individuals affected with Lethal multiple pterygium syndrome and no experimental evidence demonstrating its impact on protein function have been reported in the literature. A whole-exome sequence (WES) analysis performed at our laboratory identified the variant as a homozygote in one affected fetus with features resembling lethal multiple pterygium syndrome. The same genotype was subsequently identified in two other affected fetuses from the same family. Both parents were identified as obligate carriers and one unaffected sibling tested negative for the variant. This co-segregation with disease in one family suggests that the variant is likely to be associated with disease. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: one submitter has classified the variant as likely pathogenic while two classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001540422.5

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

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 894737). This variant has not been reported in the literature in individuals affected with CHRNA1-related conditions. This variant is present in population databases (rs779169597, gnomAD 0.08%). This sequence change affects the initiator methionine of the CHRNA1 mRNA. The next in-frame methionine is located at codon 164.

#	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: Sep 29, 2024

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