NM_170707.4(LMNA):c.1001G>A (p.Ser334Asn) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 27, 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:: RCV000653909.9

Allele description [Variation Report for NM_170707.4(LMNA):c.1001G>A (p.Ser334Asn)]

NM_170707.4(LMNA):c.1001G>A (p.Ser334Asn)

Gene:

LMNA:lamin A/C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_170707.4(LMNA):c.1001G>A (p.Ser334Asn)

HGVS:

NC_000001.11:g.156135965G>A
NG_008692.2:g.58393G>A
NM_001257374.3:c.665G>A
NM_001282624.2:c.758G>A
NM_001282625.2:c.1001G>A
NM_001282626.2:c.1001G>A
NM_005572.4:c.1001G>A
NM_170707.4:c.1001G>AMANE SELECT
NM_170708.4:c.1001G>A
NP_001244303.1:p.Ser222Asn
NP_001269553.1:p.Ser253Asn
NP_001269554.1:p.Ser334Asn
NP_001269555.1:p.Ser334Asn
NP_005563.1:p.Ser334Asn
NP_733821.1:p.Ser334Asn
NP_733822.1:p.Ser334Asn
LRG_254t2:c.1001G>A
LRG_254:g.58393G>A
NC_000001.10:g.156105756G>A
NM_001257374.1:c.665G>A
NM_170707.2:c.1001G>A
NM_170707.3:c.1001G>A

Protein change:

S222N

Links:

dbSNP: rs370656306

NCBI 1000 Genomes Browser:

rs370656306

Molecular consequence:

NM_001257374.3:c.665G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.758G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1001G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1001G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1001G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1001G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1001G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease type 2
Synonyms:: Charcot-Marie-Tooth, Type 2
Identifiers:: MONDO: MONDO:0018993; MedGen: C0270914

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DNA glycosylase superfamily protein [Arabidopsis thaliana]
DNA glycosylase superfamily protein [Arabidopsis thaliana]
gi|18398099|ref|NP_566325.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000775799	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23349452, 30847666, 32880476, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000775799

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 27, 2023)

germline

clinical testing

PubMed (4)
[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

Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience.

van Spaendonck-Zwarts KY, van Rijsingen IA, van den Berg MP, Lekanne Deprez RH, Post JG, van Mil AM, Asselbergs FW, Christiaans I, van Langen IM, Wilde AA, de Boer RA, Jongbloed JD, Pinto YM, van Tintelen JP.

Eur J Heart Fail. 2013 Jun;15(6):628-36. doi: 10.1093/eurjhf/hft013. Epub 2013 Jan 24.

PubMed [citation]

PMID:: 23349452

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

van Lint FHM, Mook ORF, Alders M, Bikker H, Lekanne Dit Deprez RH, Christiaans I.

Neth Heart J. 2019 Jun;27(6):304-309. doi: 10.1007/s12471-019-1250-5.

PubMed [citation]

PMID:: 30847666
PMCID:: PMC6533346

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000775799.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 334 of the LMNA protein (p.Ser334Asn). This variant is present in population databases (rs370656306, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 23349452, 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 161292). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LMNA protein function. 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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