rs747349942

Positions:

chr6-129401254-C-T

Variant summary

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

The NM_000426.4(LAMA2):c.5476C>T(p.Arg1826*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000059 in 1,611,364 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.741

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 6-129401254-C-T is Pathogenic according to our data. Variant chr6-129401254-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129401254-C-T is described in Lovd as [Pathogenic]. Variant chr6-129401254-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-129401254-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.5476C>T	p.Arg1826*	stop_gained	38/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.5476C>T	p.Arg1826*	stop_gained	38/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.5476C>T	p.Arg1826*	stop_gained	38/65	5	NM_000426.4	ENSP00000400365.2	P24043
LAMA2	ENST00000618192.5 linkuse as main transcript	c.5740C>T	p.Arg1914*	stop_gained	39/66	5		ENSP00000480802.2	A0A087WX80
LAMA2	ENST00000617695.5 linkuse as main transcript	c.5476C>T	p.Arg1826*	stop_gained	38/64	5		ENSP00000481744.2	A0A087WYF1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152060

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251122

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000624

AC:

AN:

1459304

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000685

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74276

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000445

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Merosin deficient congenital muscular dystrophy

Pathogenic:4

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, no assertion criteria provided	clinical testing	Counsyl	Apr 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

LAMA2-related muscular dystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2024	Variant summary: LAMA2 c.5476C>T (p.Arg1826X) 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 2.8e-05 in 251122 control chromosomes. c.5476C>T has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with Laminin Alpha 2-Related Dystrophy (example, Tan_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34702656). ClinVar contains an entry for this variant (Variation ID: 265426). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change creates a premature translational stop signal (p.Arg1826*) 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 (rs747349942, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9829280, 20207543, 24611677, 25214167). This variant is also known as c.5525C>T. ClinVar contains an entry for this variant (Variation ID: 265426). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 38 of 65). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple variants predicted to result in NMD have been reported pathogenic (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most frequently reported in patients with LAMA2-related muscular dystrophy (PMID: 30055037; ClinVar; LOVD). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2022	Previously reported multiple times in association with congenital muscular dystrophy (Geranmayeh et al., 2010; Xiong et al., 2015); Nonsense 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 (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 24611677, 9829280, 25214167, 30055037, 20207543, 32936536) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 11, 2023	- -

Muscular dystrophy, limb-girdle, autosomal recessive 23

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop-gained variant c.5476C>Tp.Arg1826Ter in the LAMA2 gene has been reported in the heterozygous and compound heterozygous state in individuals affected with Congenital muscular dystrophy Xiong et al., 2015; Savarese et al., 2014. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

The c.5476C>T (p.R1826*) alteration, located in exon 38 (coding exon 38) of the LAMA2 gene, consists of a C to T substitution at nucleotide position 5476. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1826. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the LAMA2 c.5476C>T alteration was observed in <0.01% (7/251122) of total alleles studied, with a frequency of 0.01% (2/18386) in the East Asian subpopulation. This mutation has been detected in the compound heterozygous state and confirmed in trans with a second LAMA2 alteration in several unrelated patients with congenital muscular dystrophy (Naom, 1998; Geranmayeh, 2010; Savarese, 2014; Xiong, 2015; Cauley, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Benign

-0.011

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.28

Vest4

0.79

GERP RS

1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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