NM_198129.4(LAMA3):c.7828C>T (p.Arg2610Ter) AND Junctional epidermolysis bullosa gravis of Herlitz

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 4, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000671162.2

Allele description [Variation Report for NM_198129.4(LAMA3):c.7828C>T (p.Arg2610Ter)]

NM_198129.4(LAMA3):c.7828C>T (p.Arg2610Ter)

Gene:
LAMA3:laminin subunit alpha 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q11.2
Genomic location:
Preferred name:
NM_198129.4(LAMA3):c.7828C>T (p.Arg2610Ter)
HGVS:
  • NC_000018.10:g.23916600C>T
  • NG_007853.2:g.232003C>T
  • NM_000227.6:c.3001C>T
  • NM_001127717.4:c.7660C>T
  • NM_001127718.4:c.2833C>T
  • NM_198129.4:c.7828C>TMANE SELECT
  • NP_000218.3:p.Arg1001Ter
  • NP_001121189.2:p.Arg2554Ter
  • NP_001121190.2:p.Arg945Ter
  • NP_937762.2:p.Arg2610Ter
  • NC_000018.9:g.21496564C>T
  • NM_000227.3:c.3001C>T
  • NM_000227.4:c.3001C>T
Protein change:
R1001*
Links:
dbSNP: rs768415785
NCBI 1000 Genomes Browser:
rs768415785
Molecular consequence:
  • NM_000227.6:c.3001C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001127717.4:c.7660C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001127718.4:c.2833C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_198129.4:c.7828C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Junctional epidermolysis bullosa gravis of Herlitz
Synonyms:
EPIDERMOLYSIS BULLOSA JUNCTIONALIS, HERLITZ TYPE; JEB-HERLITZ TYPE; Epidermolysis bullosa, junctional, Herlitz-Pearson type; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009182; MedGen: C0079683; Orphanet: 79404; OMIM: 226700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000796112Counsylcriteria provided, single submitter
Likely pathogenic
(Dec 1, 2017)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001362888Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Nov 4, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]
PMID:
25525159
PMCID:
PMC4362528

Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants.

Varki R, Sadowski S, Pfendner E, Uitto J.

J Med Genet. 2006 Aug;43(8):641-52. Epub 2006 Feb 10.

PubMed [citation]
PMID:
16473856
PMCID:
PMC2564586

Details of each submission

From Counsyl, SCV000796112.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362888.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: LAMA3 c.3001C>T (p.Arg1001X) 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. At-least one splice variant downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.3001C>T has been reported in the literature in compound heterozygosity with another truncating alteration in at-least one individual affected with Herlitz Junctional Epidermolysis Bullosa (hemidesmosomal variants of EB (HEB), Varki_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and another classified the variant as uncertain significance. Based on the well established etiology of loss of function variants in the pathophysiology of JEB and the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 25, 2021

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