rs768458445

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000426.4(LAMA2):c.5325dup(p.Leu1776ThrfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,940 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: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.50

Variant links:

Genes affected

LAMA2 (HGNC:6482): (laminin subunit alpha 2) Laminin, an extracellular protein, is a major component of the basement membrane. It is thought to mediate the attachment, migration, and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It is composed of three subunits, alpha, beta, and gamma, which are bound to each other by disulfide bonds into a cross-shaped molecule. This gene encodes the alpha 2 chain, which constitutes one of the subunits of laminin 2 (merosin) and laminin 4 (s-merosin). Mutations in this gene have been identified as the cause of congenital merosin-deficient muscular dystrophy. Two transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

LAMA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

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

PP5

Variant 6-129393130-G-GA is Pathogenic according to our data. Variant chr6-129393130-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.5325dup	p.Leu1776ThrfsTer3	frameshift_variant	37/65	ENST00000421865.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.5325dup	p.Leu1776ThrfsTer3	frameshift_variant	37/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LAMA2	ENST00000421865.3 linkuse as main transcript	c.5325dup	p.Leu1776ThrfsTer3	frameshift_variant	37/65	5	NM_000426.4
LAMA2	ENST00000617695.5 linkuse as main transcript	c.5325dup	p.Leu1776ThrfsTer3	frameshift_variant	37/64	5
LAMA2	ENST00000618192.5 linkuse as main transcript	c.5589dup	p.Leu1864ThrfsTer3	frameshift_variant	38/66	5		P1
LAMA2	ENST00000687590.1 linkuse as main transcript	n.1745dup		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

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:

0.000478

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251280

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135804

show subpopulations

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727188

show subpopulations

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:

0.0000549

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

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:

0.000478

Bravo

AF:

0.0000264

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

LAMA2-related muscular dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 05, 2023	This sequence change creates a premature translational stop signal (p.Leu1776Thrfs*3) in the LAMA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894, 32904964). This variant is present in population databases (rs768458445, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with muscular dystrophy (PMID: 20207543). ClinVar contains an entry for this variant (Variation ID: 551387). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2023	Variant summary: LAMA2 c.5325dupA (p.Leu1776ThrfsX3) 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 1.2e-05 in 251280 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5325dupA has been reported in the literature in at least two compound heterozygous individuals affected with Laminin Alpha 2-Related Dystrophy (e.g., Geranmayeh_2010, Oliveira_2018). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20207543, 30055037). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Merosin deficient congenital muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 07, 2017

- -

LAMA2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The LAMA2 c.5325dupA variant is predicted to result in a frameshift and premature protein termination (p.Leu1776Thrfs*3). This variant has been reported to be causative for autosomal recessive merosin-deficient congenital muscular dystrophy 1A (MCD1A) (Geranmayeh et al. 2010. PubMed ID: 20207543). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in LAMA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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