rs80356682

Positions:

chr1-209625721-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000228.3(LAMB3):c.1903C>T(p.Arg635Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,614,000 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R635R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 0 hom. )

Consequence

LAMB3
NM_000228.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 3.12

Variant links:

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]

LAMB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 1-209625721-G-A is Pathogenic according to our data. Variant chr1-209625721-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-209625721-G-A is described in Lovd as [Pathogenic]. Variant chr1-209625721-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB3	NM_000228.3 linkuse as main transcript	c.1903C>T	p.Arg635Ter	stop_gained	14/23	ENST00000356082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LAMB3	ENST00000356082.9 linkuse as main transcript	c.1903C>T	p.Arg635Ter	stop_gained	14/23	1	NM_000228.3	P1
LAMB3	ENST00000367030.7 linkuse as main transcript	c.1903C>T	p.Arg635Ter	stop_gained	14/23	1		P1
LAMB3	ENST00000391911.5 linkuse as main transcript	c.1903C>T	p.Arg635Ter	stop_gained	13/22	1		P1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000509

AC:

128

AN:

251368

Hom.:

AF XY:

0.000434

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000706

AC:

1032

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

479

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

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:

0.000225

Gnomad4 NFE exome

AF:

0.000870

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000467

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000722

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000758

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	Reported in multiple individuals with junctional epidermolysis bullosa (JEB) as the single most common JEB pathogenic variant representing 40% of the disease alleles in Caucasian patients with JEB (Pulkkinen et al., 1994; Varki et al., 2006); 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; This variant is associated with the following publications: (PMID: 27062385, 11298117, 20301304, 12366701, 11689492, 25525159, 7698759, 16473856, 11451332, 25708563, 27375110, 15311214, 15663509, 26990548, 9205497, 9209887, 8824879, 28830826, 31980526, 31589614, 32484238, 33274474) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Arg635*) 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). This variant is present in population databases (rs80356682, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive epidermolysis bullosa (PMID: 7698759, 11689492, 15311214, 15663509, 27062385, 28830826). ClinVar contains an entry for this variant (Variation ID: 14539). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Junctional epidermolysis bullosa gravis of Herlitz

Pathogenic:6Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Apr 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_000228.2(LAMB3):c.1903C>T(R635) is classified as pathogenic in the context of LAMB3-related Herlitz junctional epidermolysis bullosa. Sources cited for classification include the following: PMID 16473856, 17476356, 16473856, 11023379 and 8983017. Classification of NM_000228.2(LAMB3):c.1903C>T(R635) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2016	Variant summary: The LAMB3 c.1903C>T (p.Arg635X) variant results in a premature termination codon, predicted to cause a truncated or absent LAMB3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 92/121034 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0013392 (89/66456). This variant has been reported in numerous JEB patients both as homozygotes and compound heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 01, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -
Pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 03, 2016	- -

Junctional epidermolysis bullosa, non-Herlitz type

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 01, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.R635* in LAMB3 (NM_000228.3) have been reported previously in multiple patients associated with severe Herlitz phenotype (Nakano et al 2000; Cserhalmi-Friedman et al 2001). The variant has been reported to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. The p.R635* variant is a loss of function variant in the gene LAMB3, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000219.2:p.L11Pfs*43 and 47 others. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	LAMB3 NM_000228.2 exon 14 p.Arg635* (c.1903C>T): This variant has been reported in the literature in several individuals with epidermolysis bullosa in the homozygous and compound heterozygous state, including an entry in GeneReviews. Literature suggests that this variant is one of the most common pathogenic variants in this gene (Pulkkinen 1994 PMID:7698759, Kivirikko 1996 PMID:8824879, Varki 2006 PMID:16473856, Pfendner 2014 PMID:20301304). This variant is present in 0.1% (133/129106) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-209799066-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, autosomal recessive inheritance carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:14539). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies also support that this variant will impact the protein (Pulkkinen 1994 PMID:7698759). This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Varki 2006 PMID:16473856). In summary, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -

LAMB3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

The LAMB3 c.1903C>T variant is predicted to result in premature protein termination (p.Arg635*). This variant has been reported, in the homozygous or compound heterozygous state, in individuals affected with Herlitz type of junctional epidermolysis bullosa (see for example, Kivirikko et al. 1996. PubMed ID: 8824879; Pulkkinen et al. 1997. PubMed ID: 9242513; Christiano et al. 1997. PubMed ID: 9160387; Yuen et al. 2011. PubMed ID: 21801158). It is considered one of the most common causative variants for junctional epidermolysis bullosa (Varki et al. 2006. PubMed ID: 16473856). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and it is interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/14539/). Nonsense variants in LAMB3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Junctional epidermolysis bullosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 02, 2018

The LAMB3 c.1903C>T (p.Arg635Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg635Ter variant occurs in a region of the gene described as a mutational hotspot (Kivirikko et al. 1996; Pulkkinen et al. 1997). Nanako et al. (2000) noted that the p.Arg635Ter variant was present in 45.4% of disease-associated LAMB3 alleles in a review of a database of junctional epidermolysis bullosa(JEB) variants. Across a selection of the available literature, the p.Arg635Ter variant has been identified in 14 probands in a homozygous state and in 20 probands in a compound heterozygous state, most often associated with the severe Herlitz phenotype (Pulkkinen et al. 1994; Kivirikko et al. 1996; Pulkkinen et al. 1997; Nakano et al. 2000; Cserhalmi-Friedman et al. 2001; Gache et al. 2001; Hauschild et al. 2001). Segregation of the variant with the disease was shown in two studies (Pulkkinen et al. 1994; Gache et al. 2001). The p.Arg635Ter variant is reported at a frequency of 0.00134 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg635Ter variant is classified as 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

0.28

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.0031

FATHMM_MKL

Benign

0.70

MutationTaster

Benign

1.0

A;A;A

Vest4

0.88

GERP RS

3.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.27

Position offset: 18

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over