rs786204569

Variant names:

• chr1-209634547-G-GA
• rs776537364
• NM_000228.3:c.463dupT

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.463dupT​(p.Ser155PhefsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: LAMB3 NM_000228.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.674

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 1-209634547-G-GA is Pathogenic according to our data. Variant chr1-209634547-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.463dupT	p.Ser155PhefsTer27	frameshift_variant	Exon 6 of 23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.463dupT	p.Ser155PhefsTer27	frameshift_variant	Exon 6 of 23	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.463dupT	p.Ser155PhefsTer27	frameshift_variant	Exon 6 of 23	1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.463dupT	p.Ser155PhefsTer27	frameshift_variant	Exon 5 of 22	1		ENSP00000375778.1
LAMB3	ENST00000415782.1	c.463dupT	p.Ser155PhefsTer27	frameshift_variant	Exon 6 of 6	2		ENSP00000388960.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251300 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135848

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 727244

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: 0.0000522

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 12, 2022

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.Ser155Phefs*27) 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 (rs776537364, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 8824879, 11023379; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188937). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jun 20, 2023

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9160387, 8824879, 11023379) -

Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:2

Aug 25, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Nov 13, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The LAMB3 c.463dupT (p.Ser155PhefsX27) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1365_1366delCA, p.Asn456fsX7; c.1903C>T, p.Arg635X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/246120 control chromosomes at a frequency of 0.0000163, which does not exceed the estimated maximal expected allele frequency of a pathogenic LAMB3 variant (0.0009317). The variant has been reported in at least 3 affected individuals in the literature. In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic. -

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

Mar 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs776537364; hg19: chr1-209807892;