rs121913569

Positions:

• chr6-129315638-C-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.Gln1240Ter) 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/exons	MANE	UniProt
LAMA2	NM_000426.4	c.3718C>T	p.Gln1240Ter	stop_gained	25/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.3718C>T	p.Gln1240Ter	stop_gained	25/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.3718C>T	p.Gln1240Ter	stop_gained	25/65	5	NM_000426.4
LAMA2	ENST00000618192.5	c.3982C>T	p.Gln1328Ter	stop_gained	26/66	5		P1
LAMA2	ENST00000617695.5	c.3718C>T	p.Gln1240Ter	stop_gained	25/64	5

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1995	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 07, 2017	- -

LAMA2-related muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2023

For these reasons, this variant has been classified as Pathogenic. 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). ClinVar contains an entry for this variant (Variation ID: 14290). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 03, 2013

- -

Qualitative or quantitative defects of merosin Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

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

May 02, 2023

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
MutationTaster	Benign	1.0	A
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;