Submissions for variant NM_005562.3(LAMC2):c.283C>T (p.Arg95Ter)

dbSNP: rs80356683

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV000015656	SCV001193868	pathogenic	Junctional epidermolysis bullosa gravis of Herlitz	2019-11-11	criteria provided, single submitter	clinical testing	NM_005562.2(LAMC2):c.283C>T(R95*) is classified as pathogenic in the context of LAMC2-related junctional epidermolysis bullosa. Sources cited for classification include the following: PMID 17916201, 9085255, 15373767, 8012394 and 8983017. Classification of NM_005562.2(LAMC2):c.283C>T(R95*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV001243997	SCV001417189	pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 14555). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 8012394). This variant is present in population databases (rs80356683, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg95*) in the LAMC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMC2 are known to be pathogenic (PMID: 11907499, 16473856). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002051622	SCV002557506	pathogenic	Epidermolysis bullosa, junctional 3B, severe	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Herlitz junctional epidermolysis bullosa (MIM#226700) and non-Herlitz junctional epidermolysis bullosa (MIM#226650). (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 (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a recurrent variant in patients with junctional epidermolysis bullosa, including in the homozygous state in at least two patient with Herlitz junctional epidermolysis bullosa (ClinVar, PMID: 17916201). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV002051622	SCV000035921	pathogenic	Epidermolysis bullosa, junctional 3B, severe	2022-03-29	no assertion criteria provided	literature only
GeneReviews	RCV000015656	SCV000041152	not provided	Junctional epidermolysis bullosa gravis of Herlitz		no assertion provided	literature only