rs34505698
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_000426.4(LAMA2):c.3532G>A(p.Ala1178Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,050 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1178V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000426.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.3532G>A | p.Ala1178Thr | missense_variant | 24/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.3532G>A | p.Ala1178Thr | missense_variant | 24/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.3532G>A | p.Ala1178Thr | missense_variant | 24/65 | 5 | NM_000426.4 | ||
LAMA2 | ENST00000618192.5 | c.3796G>A | p.Ala1266Thr | missense_variant | 25/66 | 5 | P1 | ||
LAMA2 | ENST00000617695.5 | c.3532G>A | p.Ala1178Thr | missense_variant | 24/64 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000651 AC: 99AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000473 AC: 119AN: 251476Hom.: 0 AF XY: 0.000441 AC XY: 60AN XY: 135912
GnomAD4 exome AF: 0.00121 AC: 1773AN: 1461744Hom.: 3 Cov.: 32 AF XY: 0.00118 AC XY: 860AN XY: 727170
GnomAD4 genome AF: 0.000650 AC: 99AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37AN XY: 74472
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35710456) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 15, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 29, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 05, 2017 | - - |
Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 29, 2019 | - - |
LAMA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 31, 2023 | The LAMA2 c.3532G>A variant is predicted to result in the amino acid substitution p.Ala1178Thr. This variant was reported as possibly causative variant in compound heterozygous state in an individual with Psychomotor retardation and polyneuropathy (Table S1, Schobers et al 2022. PubMed ID: 35710456). This variant is reported in 0.080% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-129635920-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
LAMA2-related muscular dystrophy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at