rs750731624

Variant names:

• chr6-129287861-AT-A
• rs750731624
• NM_000426.4:c.2556delT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000426.4(LAMA2):​c.2556delT​(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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.79

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 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 rank	MANE	Protein	UniProt
LAMA2	NM_000426.4	c.2556delT	p.Phe852LeufsTer36	frameshift_variant	Exon 19 of 65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2	c.2556delT	p.Phe852LeufsTer36	frameshift_variant	Exon 19 of 64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3	c.2556delT	p.Phe852LeufsTer36	frameshift_variant	Exon 19 of 65	5	NM_000426.4	ENSP00000400365.2
LAMA2	ENST00000618192.5	c.2556delT	p.Phe852LeufsTer36	frameshift_variant	Exon 19 of 66	5		ENSP00000480802.2
LAMA2	ENST00000617695.5	c.2556delT	p.Phe852LeufsTer36	frameshift_variant	Exon 19 of 64	5		ENSP00000481744.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

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: 2 AN: 251430 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135890

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: 85 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727110

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: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:5

Jun 14, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 16, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2553delT (p.Phe852Leufs*36) 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.Phe852Leufs*36) as a recessive Likely pathogenic variant for merosin-deficient congenital muscular dystrophy. -

Jun 03, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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 protein’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). -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital merosin deficient or partially deficient muscular dystrophy (MIM#607855) and autosomal recessive limb-girdle muscular dystrophy, 23 (MIM#618138). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (86 heterozygotes, 0 homozygote). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in >10 unrelated compound heterozygous individuals with congenital muscular dystrophies (ClinVar, LOVD, PMIDs: 28688748, 27159402, 20207543). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

Feb 12, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4_moderate, PM2 -

LAMA2-related muscular dystrophy Pathogenic:1

Jan 06, 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.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

Feb 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs750731624; hg19: chr6-129609006;