6-129393184-G-T

Variant summary

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

The NM_000426.4(LAMA2):c.5374G>T(p.Glu1792Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,750 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LAMA2 NM_000426.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.51

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]

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 6-129393184-G-T is Pathogenic according to our data. Variant chr6-129393184-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 265425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129393184-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.5374G>T	p.Glu1792Ter	stop_gained	37/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.5374G>T	p.Glu1792Ter	stop_gained	37/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.5374G>T	p.Glu1792Ter	stop_gained	37/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.5638G>T	p.Glu1880Ter	stop_gained	38/66	5		P1
LAMA2	ENST00000617695.5	c.5374G>T	p.Glu1792Ter	stop_gained	37/64	5
LAMA2	ENST00000687590.1	n.1794G>T		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

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 Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LAMA2: PM3:Very Strong, PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2016	The E1792X pathogenic variant in the LAMA2 gene has been reported previously in one individual with congenital muscular dystrophy, although a second pathogenic variant was not identified in this individual (Beytia et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E1792X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret E1792X as a pathogenic variant. -

Merosin deficient congenital muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 01, 2023

- -

LAMA2-related muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2023

This sequence change creates a premature translational stop signal (p.Glu1792*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy (PMID: 24225367). ClinVar contains an entry for this variant (Variation ID: 265425). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A
Vest4		0.88
GERP RS		3.6

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: rs746201268; hg19: chr6-129714329;