rs769151482

Positions:

• chr1-209626875-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000228.3(LAMB3):​c.1587_1588delAG​(p.Gly530fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T529T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LAMB3 NM_000228.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.759

Genes affected

LAMB3 (HGNC:6490): (laminin subunit beta 3) The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-209626875-CCT-C is Pathogenic according to our data. Variant chr1-209626875-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 14548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.1587_1588delAG	p.Gly530fs	frameshift_variant	13/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.1587_1588delAG	p.Gly530fs	frameshift_variant	13/23	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.1587_1588delAG	p.Gly530fs	frameshift_variant	13/23	1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.1587_1588delAG	p.Gly530fs	frameshift_variant	12/22	1		ENSP00000375778.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250330 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460794 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 26, 2017	- -

Junctional epidermolysis bullosa gravis of Herlitz;C0268374:Junctional epidermolysis bullosa, non-Herlitz type;C4011403:Amelogenesis imperfecta type 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 11, 2024

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 14, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 14548). This variant is also known as 1587delAG. This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 11689492). This variant is present in population databases (rs769151482, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gly530Metfs*5) in the LAMB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMB3 are known to be pathogenic (PMID: 11023379, 16473856). -

Junctional epidermolysis bullosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 05, 2022

Variant summary: LAMB3 c.1587_1588delAG (p.Gly530MetfsX5) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250330 control chromosomes. c.1587_1588delAG has been reported in the literature in individuals affected with Junctional Epidermolysis Bullosa in the homozygous and compound heterozygous state (eg. Gache_2001, Posteraro_2004, Takeichi_2015). These data indicate that the variant is likely to be associated with disease. RT-PCR studies have shown the variant restores the open-reading frame of a naturally occurring out-of-frame exon 14-skipped mRNA transcript which, thus, escapes nonsense-mediated decay (Hentze and Kulozik, 1999) and can accumulate in the cells as a single mRNA species (Posteraro_2004, Takeichi_2015). RT-PCR amplification of total RNA purified from skin biopsies of a patient with the variant showed that the mutated mRNAs underwent rapid decay shortly after birth, and that illegitimate splicing of the mRNA carrying c.1587_1588delAG generated a new internally shortened transcript with advancing age, which correlated with the patient's marked improvement of skin adhesion with advancing age (Gache_2001). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769151482; hg19: chr1-209800220;