NM_000426.4:c.3718C>T

Variant names:

• chr6-129315638-C-T
• rs121913569
• NM_000426.4:c.3718C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000426.4(LAMA2):​c.3718C>T​(p.Gln1240*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: LAMA2 NM_000426.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.49

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-129315638-C-T is Pathogenic according to our data. Variant chr6-129315638-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129315638-C-T is described in Lovd as [Pathogenic]. Variant chr6-129315638-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.3718C>T	p.Gln1240*	stop_gained	Exon 25 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.3718C>T	p.Gln1240*	stop_gained	Exon 25 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.3718C>T	p.Gln1240*	stop_gained	Exon 25 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.3982C>T	p.Gln1328*	stop_gained	Exon 26 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.3718C>T	p.Gln1240*	stop_gained	Exon 25 of 64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:2

Dec 07, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

LAMA2-related muscular dystrophy Pathogenic:1

Sep 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 14290). This sequence change creates a premature translational stop signal (p.Gln1240*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital muscular dystrophy (PMID: 7550355). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Apr 03, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Qualitative or quantitative defects of merosin Pathogenic:1

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous p.Gln1240Ter variant in LAMA2 was identified in our study in one individual with muscular dystrophy. The p.Gln1240Ter variant in LAMA2 has been previously reported in two unrelated individuals with LAMA2-related muscular dystrophy (PMID: 34559299, PMID: 7550355). Of these previously reported affected individuals (PMID: 34559299, PMID: 7550355), one was a homozygote and the individual identified by our study was a homozygote, which increases the likelihood that p.Gln1240Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 14290) and has been interpreted as pathogenic by OMIM, Invitae, and Eurofins NTD LLC and as likely pathogenic by Counsyl. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1240, which is predicted to lead to a truncated or absent protein. Loss of function of the LAMA2 gene is an established disease mechanism in autosomal recessive LAMA2-related muscular dystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive LAMA2-related muscular dystrophy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.84
GERP RS		5.8

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: rs121913569; hg19: chr6-129636783;