rs202247791

chr6-129250182-A-AACGTGTTC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000426.4(LAMA2):c.1854_1861dup(p.Leu621HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,603,844 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: 0.0000028 (0 hom.)
• Consequence: LAMA2 NM_000426.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 1.23

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-129250182-A-AACGTGTTC is Pathogenic according to our data. Variant chr6-129250182-A-AACGTGTTC is described in ClinVar as [Pathogenic]. Clinvar id is 38339.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	c.1854_1861dup	p.Leu621HisfsTer7	frameshift_variant	13/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.1854_1861dup	p.Leu621HisfsTer7	frameshift_variant	13/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.1854_1861dup	p.Leu621HisfsTer7	frameshift_variant	13/65	5	NM_000426.4
LAMA2	ENST00000617695.5	c.1854_1861dup	p.Leu621HisfsTer7	frameshift_variant	13/64	5
LAMA2	ENST00000618192.5	c.1854_1861dup	p.Leu621HisfsTer7	frameshift_variant	13/66	5		P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451638 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2021	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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32266982, 31589614, 27858741, 11938437, 18700894, 30055037) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2015	- -

Merosin deficient congenital muscular dystrophy Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 22, 2023	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2016

- -

LAMA2-related muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

This sequence change creates a premature translational stop signal (p.Leu621Hisfs*7) 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 (rs202247791, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy (PMID: 18700894). ClinVar contains an entry for this variant (Variation ID: 38339). For these reasons, this variant has been classified as Pathogenic. -

Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 05, 2023

ACMG classification criteria: PVS1 very strong, PM2 moderated, PM3 moderated, PP4 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs202247791; hg19: chr6-129571327;