rs768415785

chr18-23916600-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_198129.4(LAMA3):c.7828C>T(p.Arg2610Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,694 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: LAMA3 NM_198129.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 2.89

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 11 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 18-23916600-C-T is Pathogenic according to our data. Variant chr18-23916600-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555355.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_198129.4	c.7828C>T	p.Arg2610Ter	stop_gained	60/75	ENST00000313654.14
LAMA3	NM_000227.6	c.3001C>T	p.Arg1001Ter	stop_gained	23/38	ENST00000269217.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000313654.14	c.7828C>T	p.Arg2610Ter	stop_gained	60/75	1	NM_198129.4	P1
LAMA3	ENST00000269217.11	c.3001C>T	p.Arg1001Ter	stop_gained	23/38	1	NM_000227.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251394 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135862

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: 0.00000958 AC: 14 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727150

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.000106 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 04, 2019	Variant summary: LAMA3 c.3001C>T (p.Arg1001X) 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. At-least one splice variant downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.3001C>T has been reported in the literature in compound heterozygosity with another truncating alteration in at-least one individual affected with Herlitz Junctional Epidermolysis Bullosa (hemidesmosomal variants of EB (HEB), Varki_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and another classified the variant as uncertain significance. Based on the well established etiology of loss of function variants in the pathophysiology of JEB and the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 555355). This premature translational stop signal has been observed in individual(s) with autosomal recessive epidermolysis bullosa (PMID: 16473856, 33274474). This variant is present in population databases (rs768415785, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg1001*) 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). -

LAMA3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 10, 2018

This variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	44
Dann	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.83	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.89
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: -49

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

Publications

LitVar

Other links and lift over

dbSNP: rs768415785; hg19: chr18-21496564; COSMIC: COSV52533065;