rs1158945258

chr18-23903036-CAG-C

Variant summary

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

The NM_198129.4(LAMA3):c.6232_6233del(p.Ser2078Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,609,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LAMA3 NM_198129.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.29

Genes affected

LAMA3 (HGNC:6483): (laminin subunit alpha 3) The protein encoded by this gene belongs to the laminin family of secreted molecules. Laminins are heterotrimeric molecules that consist of alpha, beta, and gamma subunits that assemble through a coiled-coil domain. Laminins are essential for formation and function of the basement membrane and have additional functions in regulating cell migration and mechanical signal transduction. This gene encodes an alpha subunit and is responsive to several epithelial-mesenchymal regulators including keratinocyte growth factor, epidermal growth factor and insulin-like growth factor. Mutations in this gene have been identified as the cause of Herlitz type junctional epidermolysis bullosa and laryngoonychocutaneous syndrome. Alternative splicing and alternative promoter usage result in multiple transcript variants. [provided by RefSeq, Dec 2014]

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 18-23903036-CAG-C is Pathogenic according to our data. Variant chr18-23903036-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 555742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_000227.6	c.1405_1406del	p.Ser469Ter	frameshift_variant	12/38	ENST00000269217.11
LAMA3	NM_198129.4	c.6232_6233del	p.Ser2078Ter	frameshift_variant	49/75	ENST00000313654.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000269217.11	c.1405_1406del	p.Ser469Ter	frameshift_variant	12/38	1	NM_000227.6
LAMA3	ENST00000313654.14	c.6232_6233del	p.Ser2078Ter	frameshift_variant	49/75	1	NM_198129.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457788 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725506

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 28, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change creates a premature translational stop signal (p.Ser469*) in the LAMA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA3 are known to be pathogenic (PMID: 10366601, 11810295, 12915477, 16473856, 17362460, 22434185, 23869449, 27827380, 28087116). This variant is present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 11810295). ClinVar contains an entry for this variant (Variation ID: 555742). For these reasons, this variant has been classified as Pathogenic. -

Junctional epidermolysis bullosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 02, 2022

Variant summary: LAMA3 c.1405_1406delAG (p.Ser469X) 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 was absent in 249934 control chromosomes (gnomAD). c.1405_1406delAG (also known as 1372delAG)has been reported in the literature in compound heterozygous individuals affected with Junctional Epidermolysis Bullosa (example: Nakano_2002). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and 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: rs1158945258; hg19: chr18-21483000;