Variant summary: LAMA3 c.151dupG (p.Val51GlyfsX4) 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 2e-05 in 251694 control chromosomes (gnomAD and publication data), exclusively reported within the South Asian subpopulation, where it has been described as a founder mutation confined to the Punjabi population (McLean_2003). The variant, c.151dupG, has been reported in the literature in several homozygous, and at least one compound heterozygous individual affected with Laryngoonychocutaneous (or Shabbir) syndrome (McLean_2003). These data indicate that the variant is very likely to be associated with disease. This publication also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant caused a frameshift with a predicted stop codon in an exon that is specific to the laminin alpha-3a isoform, however did not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site downstream, thus resulting in an N-terminal truncation of the laminin alpha-3a protein. The altered protein was demonstrated to be present in normal amount in patient derived skin biopsy material, however decreased cell-stromal junctions with reduced numbers of anchoring filaments were detected that is consistent with mechanism of the disease (McLean_2003). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000227.6(LAMA3):c.151dup (p.Val51fs)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000227.6(LAMA3):c.151dup (p.Val51fs)
Variation ID: 42049 Accession: VCV000042049.12
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 18q11.2 18: 23873194-23873195 (GRCh38) [ NCBI UCSC ] 18: 21453158-21453159 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 14, 2024 Jun 23, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_198129.4:c.4998+1534dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_000227.6:c.151dup MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000218.3:p.Val51fs frameshift NM_000227.4:c.151dupG NM_001127717.4:c.4998+1534dup intron variant NM_001127718.4:c.151dup NP_001121190.2:p.Val51fs frameshift NC_000018.10:g.23873195dup NC_000018.9:g.21453159dup NG_007853.2:g.188598dup - Protein change
- V51fs
- Other names
- -
- Canonical SPDI
- NC_000018.10:23873194:G:GG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| LAMA3 | - | - |
GRCh38 GRCh37 |
1883 | 1974 | |
| LOC126862707 | - | - | - | GRCh38 | - | 65 |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 23, 2023 | RCV001852701.6 | |
| Pathogenic (1) |
no assertion criteria provided
|
Feb 22, 2008 | RCV000020425.3 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 23, 2022 | RCV000009339.6 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Laryngo-onycho-cutaneous syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361867.2
First in ClinVar: Jun 22, 2020 Last updated: Jul 17, 2022 |
Comment:
Variant summary: LAMA3 c.151dupG (p.Val51GlyfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: LAMA3 c.151dupG (p.Val51GlyfsX4) 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 2e-05 in 251694 control chromosomes (gnomAD and publication data), exclusively reported within the South Asian subpopulation, where it has been described as a founder mutation confined to the Punjabi population (McLean_2003). The variant, c.151dupG, has been reported in the literature in several homozygous, and at least one compound heterozygous individual affected with Laryngoonychocutaneous (or Shabbir) syndrome (McLean_2003). These data indicate that the variant is very likely to be associated with disease. This publication also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant caused a frameshift with a predicted stop codon in an exon that is specific to the laminin alpha-3a isoform, however did not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site downstream, thus resulting in an N-terminal truncation of the laminin alpha-3a protein. The altered protein was demonstrated to be present in normal amount in patient derived skin biopsy material, however decreased cell-stromal junctions with reduced numbers of anchoring filaments were detected that is consistent with mechanism of the disease (McLean_2003). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002216726.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42049). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42049). This premature translational stop signal has been observed in individual(s) with laryngoonychocutaneous syndrome (PMID: 12915477). This variant is present in population databases (rs763733524, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Val51Glyfs*4) in the LAMA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA3 are known to be pathogenic (PMID: 10366601, 11810295, 12915477, 16473856, 17362460, 22434185, 23869449, 27827380, 28087116). (less)
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Laryngo-onycho-cutaneous syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318758.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12915477). The variant has been reported at least twice as pathogenic/likely pathogenic … (more)
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12915477). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042049, PMID:12915477, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000159). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Skin rash (present) , Onychogryposis (present)
|
|
|
Pathogenic
(Sep 15, 2003)
|
no assertion criteria provided
Method: literature only
|
EPIDERMOLYSIS BULLOSA, JUNCTIONAL 2C, LARYNGOONYCHOCUTANEOUS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029557.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 02, 2022 |
Comment on evidence:
In affected members of 15 consanguineous Punjabi families with laryngoonychocutaneous syndrome (JEB2C; 245660), McLean et al. (2003) identified a 1-bp insertion (151insG) in the LAMA3 … (more)
In affected members of 15 consanguineous Punjabi families with laryngoonychocutaneous syndrome (JEB2C; 245660), McLean et al. (2003) identified a 1-bp insertion (151insG) in the LAMA3 gene that caused a frameshift and a predicted stop codon in an exon that is specific to the laminin alpha-3a isoform. The mutation did not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site 6 exons downstream. The resultant N-terminal deletion of laminin alpha-3a was confirmed by immunoprecipitation of secreted proteins from LOC keratinocytes. (less)
|
|
|
pathologic
(Feb 22, 2008)
|
no assertion criteria provided
Method: curation
|
Junctional Epidermolysis Bullosa
Affected status: not provided
Allele origin:
not provided
|
GeneReviews
Accession: SCV000040829.2
First in ClinVar: Apr 04, 2013 Last updated: May 03, 2013 |
Comment:
Converted during submission to Pathogenic.
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42049). This premature translational stop signal has been observed in individual(s) with laryngoonychocutaneous syndrome (PMID: 12915477). This variant is present in population databases (rs763733524, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Val51Glyfs*4) in the LAMA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA3 are known to be pathogenic (PMID: 10366601, 11810295, 12915477, 16473856, 17362460, 22434185, 23869449, 27827380, 28087116).
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12915477). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042049, PMID:12915477, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000159). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Converted during submission to Pathogenic.
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. |
Comment:
Variant summary: LAMA3 c.151dupG (p.Val51GlyfsX4) 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 2e-05 in 251694 control chromosomes (gnomAD and publication data), exclusively reported within the South Asian subpopulation, where it has been described as a founder mutation confined to the Punjabi population (McLean_2003). The variant, c.151dupG, has been reported in the literature in several homozygous, and at least one compound heterozygous individual affected with Laryngoonychocutaneous (or Shabbir) syndrome (McLean_2003). These data indicate that the variant is very likely to be associated with disease. This publication also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant caused a frameshift with a predicted stop codon in an exon that is specific to the laminin alpha-3a isoform, however did not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site downstream, thus resulting in an N-terminal truncation of the laminin alpha-3a protein. The altered protein was demonstrated to be present in normal amount in patient derived skin biopsy material, however decreased cell-stromal junctions with reduced numbers of anchoring filaments were detected that is consistent with mechanism of the disease (McLean_2003). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42049). This premature translational stop signal has been observed in individual(s) with laryngoonychocutaneous syndrome (PMID: 12915477). This variant is present in population databases (rs763733524, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Val51Glyfs*4) in the LAMA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA3 are known to be pathogenic (PMID: 10366601, 11810295, 12915477, 16473856, 17362460, 22434185, 23869449, 27827380, 28087116).
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12915477). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042049, PMID:12915477, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000159). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Converted during submission to Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Junctional Epidermolysis Bullosa. | Adam MP | - | 2018 | PMID: 20301304 |
| Application of whole exome sequencing in elucidating the phenotype and genotype spectrum of junctional epidermolysis bullosa: A preliminary experience of a tertiary care centre in India. | Yenamandra VK | Journal of dermatological science | 2017 | PMID: 28087116 |
| Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency. | Gostyńska KB | European journal of human genetics : EJHG | 2016 | PMID: 27827380 |
| A new homozygous nonsense mutation in LAMA3A underlying laryngo-onycho-cutaneous syndrome. | Barzegar M | The British journal of dermatology | 2013 | PMID: 23869449 |
| Enamel defects in carriers of a novel LAMA3 mutation underlying epidermolysis bullosa. | Yuen WY | Acta dermato-venereologica | 2012 | PMID: 22434185 |
| Granulation tissue in the eyelid margin and conjunctiva in junctional epidermolysis bullosa with features of laryngo-onycho-cutaneous syndrome. | Figueira EC | Clinical & experimental ophthalmology | 2007 | PMID: 17362460 |
| Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. | Varki R | Journal of medical genetics | 2006 | PMID: 16473856 |
| An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. | McLean WH | Human molecular genetics | 2003 | PMID: 12915477 |
| Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. | Nakano A | Human genetics | 2002 | PMID: 11810295 |
| Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells. | Ryan MC | The Journal of cell biology | 1999 | PMID: 10366601 |
Text-mined citations for rs80356678 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.