rs202247790

Variant names:

• chr6-129252243-AAG-A
• rs202247790
• NM_000426.4:c.2049_2050delAG

Variant summary

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

The NM_000426.4(LAMA2):​c.2049_2050delAG​(p.Arg683SerfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.000145 in 1,613,960 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 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: LAMA2 NM_000426.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1 O:1
• Conservation: PhyloP100: 4.44

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 6-129252243-AAG-A is Pathogenic according to our data. Variant chr6-129252243-AAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129252243-AAG-A is described in Lovd as [Pathogenic]. Variant chr6-129252243-AAG-A is described in Lovd as [Likely_pathogenic]. Variant chr6-129252243-AAG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2049_2050delAG	p.Arg683SerfsTer21	frameshift_variant	Exon 14 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2049_2050delAG	p.Arg683SerfsTer21	frameshift_variant	Exon 14 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2049_2050delAG	p.Arg683SerfsTer21	frameshift_variant	Exon 14 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.2049_2050delAG	p.Arg683SerfsTer21	frameshift_variant	Exon 14 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.2049_2050delAG	p.Arg683SerfsTer21	frameshift_variant	Exon 14 of 64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251274 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135790

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 220 AN: 1461760 Hom.: 0 AF XY: 0.000139 AC XY: 101 AN XY: 727194

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

Gnomad4 AFR AF: 0.000121

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.0000907

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:9 Other:1

Aug 17, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 03, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 13, 2019

Breda Genetics srl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant c.2045_2046delAG (p.Arg683Serfs*21) in the LAMA2 gene is reported as pathogenic for merosin deficient congenital muscular dystrophy in ClinVar (Variation ID: 38340) and as effect unknown in the Whole Genome datasets LAMA2 LOVD database v.3.0 (genomic variant: #0000691061). This variant creates a shift in the reading frame which is predicted to result in a premature stop codon 21 amino acids downstream and is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.0001 in gnomAD exomes, 0.0001 in gnomAD genomes and 0.0002 in NHLI Exome Sequencing Project (ESP), with no homozygous individuals reported. This variant – also known in the literature as c.2049_2050del or Lys682LysfsX22 – is one of the most frequently reported pathogenic variant in the LAMA2 gene, being identified in several individuals affected by congenital muscular dystrophy (e.g. PMIDs: 9541105, 27854218, 25544356, 30055037). -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 29, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000116, PM2). The variant has been reported as pathogenic (ClinVar VCV000038340.19). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:5

Nov 08, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LAMA2: PM3:Very Strong, PVS1, PM2 -

Nov 18, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PM3_strong, PS4_moderate, PVS1 -

Aug 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed multiple times with a second pathogenic variant in unrelated individuals with merosin-deficient congenital muscular dystrophy (PMID: 9541105, 25544356, 24611677); 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; This variant is associated with the following publications: (PMID: 28133863, 28877744, 18700894, 25544356, 9541105, 27886618, 27854218, 28804634, 25663498, 31404137, 32827036, 33558818, 32528171, 37476021, 24611677, 11591858, 11369186, 28182637, 30055037, 30301903, 37206914, 36057830, 31066047, 34281576, 20207543, 36945402, 9674786, 37933889) -

LAMA2-related muscular dystrophy Pathogenic:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg683Serfs*21) 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 (rs751627052, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 9541105, 18700894, 24611677, 25544356). For these reasons, this variant has been classified as Pathogenic. -

Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Pathogenic:1

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Institute of Human Genetics, University of Wuerzburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

LAMA2-related disorder Pathogenic:1

Oct 28, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshifting variant in exon 14 of 65 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in LAMA2 is an established mechanism of disease (PMID: 22675738). This variant has been previously reported as a homozygous and compound heterozygous change in individuals with LAMA2-related disorders (PMID: 3558818, 37476021, 32827036, 25544356, 9541105). The c.2049_2050del (p.Arg683SerfsTer21) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.01% (234/1613960), and is absent in the homozygous state. Based on the available evidence, c.2049_2050del (p.Arg683SerfsTer21) is classified as Pathogenic. -

not specified Uncertain:1

Dec 01, 2015

Center for Genetic Medicine Research, Children's National Medical Center

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

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: rs202247790; hg19: chr6-129573388;