ClinVar Genomic variation as it relates to human health
NM_000426.4(LAMA2):c.7732C>T (p.Arg2578Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000426.4(LAMA2):c.7732C>T (p.Arg2578Ter)
Variation ID: 14296 Accession: VCV000014296.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q22.33 6: 129481422 (GRCh38) [ NCBI UCSC ] 6: 129802567 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 8, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000426.4:c.7732C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000417.3:p.Arg2578Ter nonsense NM_001079823.2:c.7720C>T NP_001073291.2:p.Arg2574Ter nonsense NC_000006.12:g.129481422C>T NC_000006.11:g.129802567C>T NG_008678.1:g.603282C>T LRG_409:g.603282C>T LRG_409t1:c.7732C>T LRG_409p1:p.Arg2578Ter - Protein change
- R2578*, R2574*
- Other names
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- Canonical SPDI
- NC_000006.12:129481421:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LAMA2 | - | - |
GRCh38 GRCh37 |
4880 | 5069 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 2, 2023 | RCV000015366.28 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2023 | RCV000790757.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763556.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV001068136.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 5, 2021 | RCV001794447.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 5, 2022 | RCV002288491.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 25, 2021 | RCV002513061.3 | |
LAMA2-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Feb 7, 2024 | RCV004532360.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Merosin deficient congenital muscular dystrophy
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000792200.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
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Pathogenic
(Aug 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy, limb-girdle, autosomal recessive 23
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579948.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM3, PM2_SUP
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy, limb-girdle, autosomal recessive 23
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047764.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The stop gained c.7732C>T (p.Arg2578Ter) variant has been observed in individuals with congenital muscular dystrophy (CoralVazquez RM et al). This p.Arg2578Ter variant has allele frequency … (more)
The stop gained c.7732C>T (p.Arg2578Ter) variant has been observed in individuals with congenital muscular dystrophy (CoralVazquez RM et al). This p.Arg2578Ter variant has allele frequency of 0.0053% in the gnomAD and novel (not in any individuals) in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.7732C>T in LAMA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant / CNV, the molecular diagnosis is not confirmed. (less)
Clinical Features:
Myopathy (present) , Muscular dystrophy (present)
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Pathogenic
(Jul 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Merosin deficient congenital muscular dystrophy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004190484.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Merosin deficient congenital muscular dystrophy
Muscular dystrophy, limb-girdle, autosomal recessive 23
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894373.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Apr 05, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000231362.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450346.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Congenital Muscular Dystrophy, LAMA2-related
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV002034842.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
Comment:
The LAMA2 c.7732C>T (p.Arg2578Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg2578Ter variant has … (more)
The LAMA2 c.7732C>T (p.Arg2578Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg2578Ter variant has been reported in at least eight individuals with LAMA2-related congenital muscular dystrophy including in a homozygous state in four affected individuals (including one pair of siblings), and in a compound heterozygous state in four affected individuals (Coral-Vazquez et al. 2003; Xiong et al. 2015; Incecik et al. 2015; Yiş et al. 2017; Jayakody et al. 2020 Kanzoska et al. 2021). Additionally, six unaffected heterozygous carriers were identified in one family (Coral-Vazquez et al. 2003). The variant is found at a frequency of 0.000085 in the Latino/Admixed American population of the Genome Aggregation Database (version 2.1.1). Based on the evidence, the p.Arg2578Ter variant is classified as pathogenic for LAMA2-related congenital muscular dystrophy. (less)
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Pathogenic
(Apr 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002578718.2
First in ClinVar: Oct 15, 2022 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss of function is a known mechanism of disease; … (more)
Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32342562, 29212164, 32827036, 33726816, 26962340, 12601554, 29376585) (less)
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Pathogenic
(Jan 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003818955.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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LAMA2-related muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001233226.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg2578*) in the LAMA2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg2578*) 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 (rs121913572, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy (PMID: 12601554, 20207543, 21520333, 24611677). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 14296). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003746427.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.7732C>T (p.R2578*) alteration, located in exon 55 (coding exon 55) of the LAMA2 gene, consists of a C to T substitution at nucleotide position … (more)
The c.7732C>T (p.R2578*) alteration, located in exon 55 (coding exon 55) of the LAMA2 gene, consists of a C to T substitution at nucleotide position 7732. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 2578. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation has been reported in several individuals with LAMA2-related muscular dystrophy in both the homozygous and compound heterozygous states (Coral-Vazquez, 2003; Geranmayeh, 2010; Xiong, 2015; Yi, 2017; Jayakody, 2020). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Nov 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821769.13
First in ClinVar: Jan 21, 2023 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Jan 01, 2003)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY, CONGENITAL MEROSIN-DEFICIENT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035627.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Coral-Vazquez et al. (2003) reported the case of an 8-month-old Mexican female, from a consanguineous family, with classic merosin-deficient congenital muscular dystrophy (607855). In addition … (more)
Coral-Vazquez et al. (2003) reported the case of an 8-month-old Mexican female, from a consanguineous family, with classic merosin-deficient congenital muscular dystrophy (607855). In addition to elevated serum creatine kinase and dystrophic changes on muscle biopsy, there were abnormalities on brain MRI. Immunofluorescence analysis demonstrated complete absence of LAMA2. In contrast, all components of the dystrophin-glycoprotein complex appeared normal. Mutation analysis of the LAMA2 gene identified a homozygous 7781C-T transition in exon 54 that resulted in an arg2578-to-ter (R2578X) mutation in the G domain of the protein. Both parents and some other relatives were carriers of the mutation. (less)
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Pathogenic
(Feb 07, 2024)
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no assertion criteria provided
Method: clinical testing
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LAMA2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004744814.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The LAMA2 c.7732C>T variant is predicted to result in premature protein termination (p.Arg2578*). This variant was reported to be causative for autosomal recessive congenital muscular … (more)
The LAMA2 c.7732C>T variant is predicted to result in premature protein termination (p.Arg2578*). This variant was reported to be causative for autosomal recessive congenital muscular dystrophy (Coral-Vazquez et al. 2003. PubMed ID: 12601554; Jayakody et al. 2020. PubMed ID: 32827036). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in LAMA2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Limb girdle muscular dystrophy due to LAMA2 gene mutations: new mutations expand the clinical spectrum of a still challenging diagnosis. | Magri F | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2020 | PMID: 32904964 |
Cobblestone Malformation in LAMA2 Congenital Muscular Dystrophy (MDC1A). | Jayakody H | Journal of neuropathology and experimental neurology | 2020 | PMID: 32827036 |
Occipital cortex dysgenesis with white matter changes due to mutations in Laminin a2. | Yiş U | The Turkish journal of pediatrics | 2017 | PMID: 29376585 |
Merosin-negative congenital muscular dystrophy: Report of five cases. | Incecik F | Journal of pediatric neurosciences | 2015 | PMID: 26962340 |
Genotype/phenotype analysis in Chinese laminin-α2 deficient congenital muscular dystrophy patients. | Xiong H | Clinical genetics | 2015 | PMID: 24611677 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations. | Geranmayeh F | Neuromuscular disorders : NMD | 2010 | PMID: 20207543 |
LAMA2 gene analysis in a cohort of 26 congenital muscular dystrophy patients. | Oliveira J | Clinical genetics | 2008 | PMID: 18700894 |
Severe congenital muscular dystrophy in a Mexican family with a new nonsense mutation (R2578X) in the laminin alpha-2 gene. | Coral-Vazquez RM | Journal of human genetics | 2003 | PMID: 12601554 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LAMA2 | - | - | - | - |
Text-mined citations for rs121913572 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.