6-129486605-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000426.4(LAMA2):c.7881T>G(p.His2627Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H2627H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LAMA2 NM_000426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: -1.07

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 6-129486605-T-G is Pathogenic according to our data. Variant chr6-129486605-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38341.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr6-129486605-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA2	NM_000426.4	c.7881T>G	p.His2627Gln	missense_variant	56/65	ENST00000421865.3
LAMA2	NM_001079823.2	c.7869T>G	p.His2623Gln	missense_variant	55/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA2	ENST00000421865.3	c.7881T>G	p.His2627Gln	missense_variant	56/65	5	NM_000426.4
	ENST00000665046.1	n.975+16000A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461602 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Merosin deficient congenital muscular dystrophy Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 17, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 05, 2016	The observed variant c.7881T>G (p.H2627Q) is not reported in The 1000 Genomes or ExAC databases. However, it is reported by Geranmayeh et al., 2010. The in silico prediction of the variant is damaging by MutationTaster2, tolerated by SIFT. -

LAMA2-related muscular dystrophy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2023	Variant summary: LAMA2 c.7881T>G (p.His2627Gln) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. However, several computational tools predict a significant impact on normal splicing: four predict the variant creates a 5' donor site seventeen nucleotides upstream of the wild-type donor site, potentially leading to a frameshift. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251070 control chromosomes (gnomAD). c.7881T>G has been reported in the literature in at least seven homozygous individuals from a single family who were affected with Laminin Alpha 2-Related Dystrophy, and all showed absent merosin (e.g., Geranmayeh_2010, Sframeli_2017, Zambon_2020, Bajaj_2022 (no PMID)). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20207543, 28688748, 32910545). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014: three submitters classified the variant as likely pathogenic and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2627 of the LAMA2 protein (p.His2627Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital muscular dystrophy (PMID: 20207543). ClinVar contains an entry for this variant (Variation ID: 38341). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LAMA2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	12
Dann	Benign	0.61
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.030	N
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.53	T
Polyphen		0.83	.;.;P
Vest4		0.42
MutPred		0.47		.;.;Loss of sheet (P = 0.0817);
MVP		0.42
MPC		0.29
ClinPred		0.42	T
GERP RS		-11
Varity_R		0.098
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: 0
DS_DL_spliceai		0.20		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202247792; hg19: chr6-129807750;