NM_000079.4(CHRNA1):c.1A>G (p.Met1Val) AND Lethal multiple pterygium syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 21, 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:: RCV002266219.3

Allele description [Variation Report for NM_000079.4(CHRNA1):c.1A>G (p.Met1Val)]

NM_000079.4(CHRNA1):c.1A>G (p.Met1Val)

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.1A>G (p.Met1Val)

HGVS:

NC_000002.12:g.174764394T>C
NG_008172.1:g.5079A>G
NM_000079.4:c.1A>GMANE SELECT
NM_001039523.3:c.1A>G
NP_000070.1:p.Met1Val
NP_001034612.1:p.Met1Val
NC_000002.11:g.175629122T>C
NM_000079.3:c.1A>G

Protein change:

M1V

Links:

dbSNP: rs146464862

NCBI 1000 Genomes Browser:

rs146464862

Molecular consequence:

NM_000079.4:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001039523.3:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000079.4:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001039523.3:c.1A>G - 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
SCV002547812	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 9, 2022)	germline	clinical testing	Citation Link,
SCV004369397	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 21, 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

SCV002547812

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(May 9, 2022)

germline

clinical testing

Citation Link,

SCV004369397

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 21, 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002547812.2

#	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.1A>G (p.Met1?, aka p.Met1Val) alters the initiation codon 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. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 (i.e.in 5 heterozygous carriers) in 150962 control chromosomes (gnomAD v3.1, genomes dataset). The presence of the variant in healthy heterozygous individuals suggests that the variant is likely not associated with disease in a dominant manner. To our knowledge, no occurrence of c.1A>G in individuals affected with Lethal Multiple Pterygium Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. On the other hand, a whole-exome sequencing (WES) analysis performed at our laboratory identified another start-loss variant (c.2T>C) in homozygous state in three affected fetuses with features resembling lethal multiple pterygium syndrome from the same family, while both parents were identified as obligate carriers and one unaffected sibling tested negative for the variant. Co-segregation with disease in one family for a similar start-loss variant suggests that the variant is likely to be associated with 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004369397.1

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

Description

This sequence change affects the initiator methionine of the CHRNA1 mRNA. The next in-frame methionine is located at codon 164. This variant is present in population databases (rs146464862, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CHRNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1696075). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

#	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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