rs750731624

Positions:

chr6-129287861-AT-A

Variant summary

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

The NM_000426.4(LAMA2):c.2556del(p.Phe852LeufsTer36) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000533 in 1,613,756 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.79

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 6-129287861-AT-A is Pathogenic according to our data. Variant chr6-129287861-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 477455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129287861-AT-A 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.2556del	p.Phe852LeufsTer36	frameshift_variant	19/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.2556del	p.Phe852LeufsTer36	frameshift_variant	19/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LAMA2	ENST00000421865.3 linkuse as main transcript	c.2556del	p.Phe852LeufsTer36	frameshift_variant	19/65	5	NM_000426.4	ENSP00000400365
LAMA2	ENST00000618192.5 linkuse as main transcript	c.2556del	p.Phe852LeufsTer36	frameshift_variant	19/66	5		ENSP00000480802	P1
LAMA2	ENST00000617695.5 linkuse as main transcript	c.2556del	p.Phe852LeufsTer36	frameshift_variant	19/64	5		ENSP00000481744

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251430

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000582

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000747

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Merosin deficient congenital muscular dystrophy

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 16, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 03, 2020	The heterozygous p.Phe852LeufsTer36 variant in LAMA2 was identified by our study in 1 individual with congenital merosin-deficient muscular dystrophy 1A. The variant has been reported in 2 individuals of unknown ethnicity with congenital merosin-deficient muscular dystrophy (PMID: 20207543), and has been identified in 0.002% (2/113710) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs750731624). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 477455) as pathogenic by Counsyl and Invitae, and as likely pathogenic by Knight Diagnostic Laboratories and Oregon Health and Sciences University. The presence of this variant in combination with reported likely pathogenic variants, and in 2 individuals with congenital merosin-deficient muscular dystrophy, increases the likelihood that the variant is pathogenic (Variation ID: 550992, 92954; PMID: 20207543). This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 852 and leads to a premature termination codon 36 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LAMA2 gene is an established disease mechanism in autosomal recessive congenital merosin-deficient muscular dystrophy. In summary, this variant meets criteria to be classified as pathogenic for congenital merosin-deficient muscular dystrophy in an autosomal recessive manner based on the predicted impact of the variant, limited appearance in control populations, and the presence of this variant in combination with pathogenic and likely pathogenic variants. ACMG/AMP Criteria applied: PVS1, PM2, PM3_supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 14, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 04, 2015	The c.2553delT (p.Phe852Leufs36) frameshift variant in the LAMA2 gene has been previously reported in two affected unrelated individuals with autosomal recessive merosin-deficient congenital muscular dystrophy and is predicted to cause premature protein termination in exon 19 (out of a total of 65 exons in the coding sequence). Both affected individuals harbored this frameshift variant in trans with either a second frameshift variant or a canonical splice site variant (Geranmayeh et al., 2010). Frameshift variants have been described in the LAMA2 gene in several affected individuals (Geranmayeh et al., 2010) and are, therefore, a common mechanism of disease. Therefore, this collective evidence supports the classification of the c.2553delT (p.Phe852Leufs36) as a recessive Likely pathogenic variant for merosin-deficient congenital muscular dystrophy. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2019	PVS1, PS4_moderate, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 12, 2020	- -

LAMA2-related muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change creates a premature translational stop signal (p.Phe852Leufs*36) 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 (rs750731624, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy (CMD) (PMID: 20207543). ClinVar contains an entry for this variant (Variation ID: 477455). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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