6-129252243-AAG-A

Position:

• chr6-129252243-AAG-A

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_2050del​(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:15 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/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2049_2050del	p.Arg683SerfsTer21	frameshift_variant	14/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2049_2050del	p.Arg683SerfsTer21	frameshift_variant	14/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2049_2050del	p.Arg683SerfsTer21	frameshift_variant	14/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000617695.5	c.2049_2050del	p.Arg683SerfsTer21	frameshift_variant	14/64	5		ENSP00000481744
LAMA2	ENST00000618192.5	c.2049_2050del	p.Arg683SerfsTer21	frameshift_variant	14/66	5		ENSP00000480802	P1

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:15 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:9 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 09, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2. -
Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Mar 13, 2019	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). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 01, 2024	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 31, 2021	PP4, PM2, PM3_strong, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LAMA2: PM3:Very Strong, PVS1, PM2 -

LAMA2-related muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

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). ClinVar contains an entry for this variant (Variation ID: 38340). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, flagged submission

research

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

Dec 01, 2015

- -

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;