NM_000426.4(LAMA2):c.939_940del (p.Cys314fs) AND LAMA2-related muscular dystrophy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 10, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000554369.9

Allele description [Variation Report for NM_000426.4(LAMA2):c.939_940del (p.Cys314fs)]

NM_000426.4(LAMA2):c.939_940del (p.Cys314fs)

Gene:

LAMA2:laminin subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

6q22.33

Genomic location:

Preferred name:

NM_000426.4(LAMA2):c.939_940del (p.Cys314fs)

HGVS:

NC_000006.12:g.129149008_129149009del
NG_008678.1:g.270868_270869del
NM_000426.4:c.939_940delMANE SELECT
NM_001079823.2:c.939_940del
NP_000417.2:p.Cys314fs
NP_000417.3:p.Cys314fs
NP_001073291.2:p.Cys314fs
LRG_409t1:c.939_940del
LRG_409:g.270868_270869del
LRG_409p1:p.Cys314fs
NC_000006.11:g.129470153_129470154del
NM_000426.3:c.939_940del
NM_000426.3:c.939_940delAT
NM_000426.4:c.939_940delATMANE SELECT

Protein change:

C314fs

Links:

dbSNP: rs1209130981

NCBI 1000 Genomes Browser:

rs1209130981

Molecular consequence:

NM_000426.4:c.939_940del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079823.2:c.939_940del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: LAMA2-related muscular dystrophy (LAMA2-RD)
Synonyms:: Laminin alpha 2-related dystrophy
Identifiers:: MONDO: MONDO:0100228; MedGen: C5679788

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000658805	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18700894, 32904964, 30055037, 28492532
SCV004803355	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005399865	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 10, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30055037, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000658805

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004803355

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV005399865

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 10, 2024)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

LAMA2 gene analysis in a cohort of 26 congenital muscular dystrophy patients.

Oliveira J, Santos R, Soares-Silva I, Jorge P, Vieira E, Oliveira ME, Moreira A, Coelho T, Ferreira JC, Fonseca MJ, Barbosa C, Prats J, Aríztegui ML, Martins ML, Moreno T, Heinimann K, Barbot C, Pascual-Pascual SI, Cabral A, Fineza I, Santos M, Bronze-da-Rocha E.

Clin Genet. 2008 Dec;74(6):502-12. doi: 10.1111/j.1399-0004.2008.01068.x. Epub 2008 Jun 11.

PubMed [citation]

PMID:: 18700894

Limb girdle muscular dystrophy due to LAMA2 gene mutations: new mutations expand the clinical spectrum of a still challenging diagnosis.

Magri F, Brusa R, Bello L, Peverelli L, Del Bo R, Govoni A, Cinnante C, Colombo I, Fortunato F, Tironi R, Corti S, Grimoldi N, Sciacco M, Bresolin N, Pegoraro E, Moggio M, Comi GP.

Acta Myol. 2020 Jun;39(2):67-82. doi: 10.36185/2532-1900-009.

PubMed [citation]

PMID:: 32904964
PMCID:: PMC7460730

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000658805.6

#	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 creates a premature translational stop signal (p.Cys314Trpfs*3) in the LAMA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894, 32904964). This variant is present in population databases (no rsID available, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 30055037). ClinVar contains an entry for this variant (Variation ID: 477529). For these reasons, this variant has been classified as 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004803355.1

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

Description

Variant summary: LAMA2 c.939_940delAT (p.Cys314TrpfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 251318 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.939_940delAT has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Laminin Alpha 2-Related Dystrophy (e.g., Oliveira_2018). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 30055037). ClinVar contains an entry for this variant (Variation ID: 477529). Based on the evidence outlined above, the variant was classified as 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005399865.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with LAMA2-related muscular dystrophy (MONDO:0100228). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (8 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported five times as pathogenic, and once as likely pathogenic in ClinVar by clinical laboratories. This variant has been observed in multiple individuals with congenital muscular dystrophy, type 1A (MDC1A) (PMID: 30055037). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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