rs1057517096

Positions:

• chr1-209629752-G-A

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.1117C>T​(p.Gln373Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q373Q) 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 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.28

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 1-209629752-G-A is Pathogenic according to our data. Variant chr1-209629752-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB3	NM_000228.3	c.1117C>T	p.Gln373Ter	stop_gained	10/23	ENST00000356082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB3	ENST00000356082.9	c.1117C>T	p.Gln373Ter	stop_gained	10/23	1	NM_000228.3	P1
LAMB3	ENST00000367030.7	c.1117C>T	p.Gln373Ter	stop_gained	10/23	1		P1
LAMB3	ENST00000391911.5	c.1117C>T	p.Gln373Ter	stop_gained	9/22	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251412 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727230

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22931927, 11023379, 25950805, 15538630, 28830826) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 17, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371216). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 11023379, 25950805, 28830826). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln373*) 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, non-Herlitz type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pars Genome Lab

-

- -

Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 02, 2016

- -

Junctional epidermolysis bullosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 30, 2018

The LAMB3 c.1117C>T (p.Gln373Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. It has been reported in two studies in which is found in a compound heterozygous state with the recurrent LAMB3 variant, p.Arg635Ter, in three affected individuals. All three individuals presented with a severe, neonatal-lethal form of junctional epidermolysis bullosa known as Herlitz disease or H-JEB. (Muhle et al. 2005; Tolar et al. 2013) Control data are unavailable for this variant, which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Skin biopsy studies showed reduced laminin-5 expression in two probands (Muhle et al. 2005) and absence of laminin B3 chain at the dermal epidermal junction in one proband (Tolar et al. 2013). Based on the evidence, the variant is classified as likely pathogenic for junctional epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Benign	0.12
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.42	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.67
GERP RS		0.71

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: rs1057517096; hg19: chr1-209803097;