rs1553277702

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000228.3(LAMB3):c.958_1034dupGGGCACTCAGAGACATGTCACTTTGACCCCGCTGTGTTTGCCGCCAGCCAGGGGGCATATGGAGGTGTGTGTGACAA(p.Asn345LysfsTer77) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LAMB3
NM_000228.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.737

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

junctional epidermolysis bullosa
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
junctional epidermolysis bullosa Herlitz type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Laboratory for Molecular Medicine
junctional epidermolysis bullosa, non-Herlitz type
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Ambry Genetics
amelogenesis imperfecta type 1A
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
amelogenesis imperfecta type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
generalized junctional epidermolysis bullosa non-Herlitz type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LAMB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-209629834-A-ATTGTCACACACACCTCCATATGCCCCCTGGCTGGCGGCAAACACAGCGGGGTCAAAGTGACATGTCTCTGAGTGCCC is Pathogenic according to our data. Variant chr1-209629834-A-ATTGTCACACACACCTCCATATGCCCCCTGGCTGGCGGCAAACACAGCGGGGTCAAAGTGACATGTCTCTGAGTGCCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 279829.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB3	NM_000228.3 link	c.958_1034dupGGGCACTCAGAGACATGTCACTTTGACCCCGCTGTGTTTGCCGCCAGCCAGGGGGCATATGGAGGTGTGTGTGACAA	p.Asn345LysfsTer77	frameshift_variant	Exon 10 of 23	ENST00000356082.9	NP_000219.2	Q13751A0A0S2Z3R6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMB3	ENST00000356082.9 link	c.958_1034dupGGGCACTCAGAGACATGTCACTTTGACCCCGCTGTGTTTGCCGCCAGCCAGGGGGCATATGGAGGTGTGTGTGACAA	p.Asn345LysfsTer77	frameshift_variant	Exon 10 of 23	1	NM_000228.3	ENSP00000348384.3	Q13751
LAMB3	ENST00000367030.7 link	c.958_1034dupGGGCACTCAGAGACATGTCACTTTGACCCCGCTGTGTTTGCCGCCAGCCAGGGGGCATATGGAGGTGTGTGTGACAA	p.Asn345LysfsTer77	frameshift_variant	Exon 10 of 23	1		ENSP00000355997.3	Q13751
LAMB3	ENST00000391911.5 link	c.958_1034dupGGGCACTCAGAGACATGTCACTTTGACCCCGCTGTGTTTGCCGCCAGCCAGGGGGCATATGGAGGTGTGTGTGACAA	p.Asn345LysfsTer77	frameshift_variant	Exon 9 of 22	1		ENSP00000375778.1	Q13751

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000870

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000437

AC:

AN:

251456

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.000689

AC:

AN:

33384

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.568

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000269

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000940

AC:

AN:

41488

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Junctional epidermolysis bullosa gravis of Herlitz

Pathogenic:3

Mar 18, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderated, PM2 moderated, PM3 supporting -

Apr 29, 2021

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Dec 01, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Sep 25, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift 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: 27375110, 7550237, 16473856) -

Jul 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Asn345Lysfs*77) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal recessive junctional epidermolysis bullosa (PMID: 16473856, 27480391). This variant is also known as 957ins77. ClinVar contains an entry for this variant (Variation ID: 279829). For these reasons, this variant has been classified as Pathogenic. -

Junctional epidermolysis bullosa, non-Herlitz type

Pathogenic:1

Dec 01, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LAMB3-related disorder

Pathogenic:1

Oct 25, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The LAMB3 c.958_1034dup77 variant is predicted to result in a frameshift and premature protein termination (p.Asn345Lysfs*77). This variant is also referred to as c.957ins77 in the literature. It has been reported in multiple individuals with junctional epidermolysis bullosa (Table 1, Nakano et al. 2000. PubMed ID: 11023379; Varki et al. 2006. PubMed ID: 16473856; reported in the compound heterozygous state in Fuentes et al. 2017. PubMed ID: 27480391). This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD (gnomad.broadinstitute.org). Frameshift variants in LAMB3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Junctional epidermolysis bullosa

Pathogenic:1

Mar 07, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LAMB3 c.958_1034dup77 (p.Asn345LysfsX77) 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 4.4e-05 in 251456 control chromosomes. This variant has been reported in multiple patients with junctional epidermolysis bullosa (Fuentes BJD_2017). One patient carrying this variant and another pathogenic LAMB3 variant showed absence of laminin beta3 chain. The following publication have been ascertained in the context of this evaluation (PMID: 27480391). ClinVar contains an entry for this variant (Variation ID: 279829). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over