NM_170707.4(LMNA):c.1619T>A (p.Met540Lys) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 22, 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:: RCV003744337.2

Allele description [Variation Report for NM_170707.4(LMNA):c.1619T>A (p.Met540Lys)]

NM_170707.4(LMNA):c.1619T>A (p.Met540Lys)

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.1619T>A (p.Met540Lys)

HGVS:

NC_000001.11:g.156137664T>A
NG_008692.2:g.60092T>A
NM_001257374.3:c.1283T>A
NM_001282624.2:c.1376T>A
NM_001282625.2:c.1619T>A
NM_001282626.2:c.1619T>A
NM_001406983.1:c.1619T>A
NM_001406984.1:c.1619T>A
NM_001406985.1:c.1619T>A
NM_001406986.1:c.1376T>A
NM_001406987.1:c.1376T>A
NM_001406988.1:c.1322T>A
NM_001406989.1:c.1283T>A
NM_001406990.1:c.1061T>A
NM_001406991.1:c.1619T>A
NM_001406992.1:c.1619T>A
NM_001406993.1:c.1061T>A
NM_001406994.1:c.995T>A
NM_001406995.1:c.1061T>A
NM_001406996.1:c.1061T>A
NM_001406997.1:c.1061T>A
NM_001406998.1:c.1283T>A
NM_001406999.1:c.995T>A
NM_001407000.1:c.995T>A
NM_001407001.1:c.995T>A
NM_001407002.1:c.1061T>A
NM_001407003.1:c.1061T>A
NM_005572.4:c.1619T>A
NM_170707.4:c.1619T>AMANE SELECT
NM_170708.4:c.1608+432T>A
NP_001244303.1:p.Met428Lys
NP_001269553.1:p.Met459Lys
NP_001269554.1:p.Met540Lys
NP_001269555.1:p.Met540Lys
NP_001393912.1:p.Met540Lys
NP_001393913.1:p.Met540Lys
NP_001393914.1:p.Met540Lys
NP_001393915.1:p.Met459Lys
NP_001393916.1:p.Met459Lys
NP_001393917.1:p.Met441Lys
NP_001393918.1:p.Met428Lys
NP_001393919.1:p.Met354Lys
NP_001393920.1:p.Met540Lys
NP_001393921.1:p.Met540Lys
NP_001393922.1:p.Met354Lys
NP_001393923.1:p.Met332Lys
NP_001393924.1:p.Met354Lys
NP_001393925.1:p.Met354Lys
NP_001393926.1:p.Met354Lys
NP_001393927.1:p.Met428Lys
NP_001393928.1:p.Met332Lys
NP_001393929.1:p.Met332Lys
NP_001393930.1:p.Met332Lys
NP_001393931.1:p.Met354Lys
NP_001393932.1:p.Met354Lys
NP_005563.1:p.Met540Lys
NP_005563.1:p.Met540Lys
NP_733821.1:p.Met540Lys
NP_733821.1:p.Met540Lys
LRG_254t1:c.1619T>A
LRG_254t2:c.1619T>A
LRG_254:g.60092T>A
LRG_254p1:p.Met540Lys
LRG_254p2:p.Met540Lys
NC_000001.10:g.156107455T>A
NM_005572.3:c.1619T>A
NM_170707.2:c.1619T>A
NR_047544.1:n.2260T>A
NR_047545.1:n.1507T>A

Protein change:

M332K

Molecular consequence:

NM_170708.4:c.1608+432T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001257374.3:c.1283T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1376T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1619T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1619T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406983.1:c.1619T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406984.1:c.1619T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406985.1:c.1619T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406986.1:c.1376T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406987.1:c.1376T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406988.1:c.1322T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406989.1:c.1283T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406990.1:c.1061T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406991.1:c.1619T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406992.1:c.1619T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406993.1:c.1061T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406994.1:c.995T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406995.1:c.1061T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406996.1:c.1061T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406997.1:c.1061T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406998.1:c.1283T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406999.1:c.995T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407000.1:c.995T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407001.1:c.995T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407002.1:c.1061T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407003.1:c.1061T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1619T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1619T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004429924	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 22, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16825282, 24639906, 26602028, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004429924

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 22, 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

Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.

Verstraeten VL, Broers JL, van Steensel MA, Zinn-Justin S, Ramaekers FC, Steijlen PM, Kamps M, Kuijpers HJ, Merckx D, Smeets HJ, Hennekam RC, Marcelis CL, van den Wijngaard A.

Hum Mol Genet. 2006 Aug 15;15(16):2509-22. Epub 2006 Jul 6.

PubMed [citation]

PMID:: 16825282

Mandibuloacral Dysplasia Caused by LMNA Mutations and Uniparental Disomy.

Bai S, Lozada A, Jones MC, Dietz HC, Dempsey M, Das S.

Case Rep Genet. 2014;2014:508231. doi: 10.1155/2014/508231. Epub 2014 Feb 3.

PubMed [citation]

PMID:: 24639906
PMCID:: PMC3930135

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004429924.1

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

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 540 of the LMNA protein (p.Met540Lys). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. 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. This variant disrupts the p.Met540 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 16825282, 24639906, 26602028), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt LMNA protein function.

#	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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