6-129481422-C-T

Variant names:

Variant summary

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

The NM_000426.4(LAMA2):c.7732C>T(p.Arg2578*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,630 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: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 3.13

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:

LOC124901401 (HGNC:):

LOC124901401 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 6-129481422-C-T is Pathogenic according to our data. Variant chr6-129481422-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129481422-C-T is described in Lovd as [Pathogenic]. Variant chr6-129481422-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LAMA2	NM_000426.4 link	c.7732C>T	p.Arg2578*	stop_gained	Exon 55 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 link	c.7720C>T	p.Arg2574*	stop_gained	Exon 54 of 64		NP_001073291.2
LOC124901401	XR_007059767.1 link	n.4961G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 link	c.7732C>T	p.Arg2578*	stop_gained	Exon 55 of 65	5	NM_000426.4	ENSP00000400365.2		P24043

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251304

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Apr 05, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 32342562, 29212164, 32827036, 33726816, 26962340, 12601554, 29376585) -

Merosin deficient congenital muscular dystrophy

Pathogenic:4

Jul 02, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Stop-gained (nonsense): 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000014296 /PMID: 12601554). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 09, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Muscular dystrophy, limb-girdle, autosomal recessive 23

Pathogenic:2

Aug 05, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained c.7732C>T (p.Arg2578Ter) variant has been observed in individuals with congenital muscular dystrophy (CoralVazquez RM et al). This p.Arg2578Ter variant has allele frequency of 0.0053% in the gnomAD and novel (not in any individuals) in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.7732C>T in LAMA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant / CNV, the molecular diagnosis is not confirmed. -

Inborn genetic diseases

Pathogenic:1

Jun 25, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7732C>T (p.R2578*) alteration, located in exon 55 (coding exon 55) of the LAMA2 gene, consists of a C to T substitution at nucleotide position 7732. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 2578. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation has been reported in several individuals with LAMA2-related muscular dystrophy in both the homozygous and compound heterozygous states (Coral-Vazquez, 2003; Geranmayeh, 2010; Xiong, 2015; Yi, 2017; Jayakody, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

LAMA2-related muscular dystrophy

Pathogenic:1

Jan 07, 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.Arg2578*) 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 (rs121913572, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy (PMID: 12601554, 20207543, 21520333, 24611677). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 14296). For these reasons, this variant has been classified as Pathogenic. -

Congenital Muscular Dystrophy, LAMA2-related

Pathogenic:1

Nov 05, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LAMA2 c.7732C>T (p.Arg2578Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg2578Ter variant has been reported in at least eight individuals with LAMA2-related congenital muscular dystrophy including in a homozygous state in four affected individuals (including one pair of siblings), and in a compound heterozygous state in four affected individuals (Coral-Vazquez et al. 2003; Xiong et al. 2015; Incecik et al. 2015; Yiş et al. 2017; Jayakody et al. 2020 Kanzoska et al. 2021). Additionally, six unaffected heterozygous carriers were identified in one family (Coral-Vazquez et al. 2003). The variant is found at a frequency of 0.000085 in the Latino/Admixed American population of the Genome Aggregation Database (version 2.1.1). Based on the evidence, the p.Arg2578Ter variant is classified as pathogenic for LAMA2-related congenital muscular dystrophy. -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LAMA2-related disorder

Pathogenic:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LAMA2 c.7732C>T variant is predicted to result in premature protein termination (p.Arg2578*). This variant was reported to be causative for autosomal recessive congenital muscular dystrophy (Coral-Vazquez et al. 2003. PubMed ID: 12601554; Jayakody et al. 2020. PubMed ID: 32827036). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in LAMA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

Vest4

0.81

GERP RS

4.5

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