Submissions for variant NM_000227.6(LAMA3):c.151dup (p.Val51fs)

dbSNP: rs80356678

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000009339	SCV001361867	pathogenic	Laryngo-onycho-cutaneous syndrome	2022-05-23	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852701	SCV002216726	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing	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).
3billion	RCV000009339	SCV002318758	pathogenic	Laryngo-onycho-cutaneous syndrome	2022-03-22	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000009339	SCV000029557	pathogenic	Laryngo-onycho-cutaneous syndrome	2003-09-15	no assertion criteria provided	literature only
GeneReviews	RCV000020425	SCV000040829	pathologic	Junctional epidermolysis bullosa gravis of Herlitz	2008-02-22	no assertion criteria provided	curation	Converted during submission to Pathogenic.