chr6-129143976-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_000426.4(LAMA2):c.715C>T(p.Arg239Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000147 in 1,612,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R239H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000426.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.715C>T | p.Arg239Cys | missense_variant | 5/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.715C>T | p.Arg239Cys | missense_variant | 5/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.715C>T | p.Arg239Cys | missense_variant | 5/65 | 5 | NM_000426.4 |
Frequencies
GnomAD3 genomes AF: 0.0000856 AC: 13AN: 151940Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000598 AC: 15AN: 250794Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135528
GnomAD4 exome AF: 0.000153 AC: 224AN: 1460102Hom.: 0 Cov.: 30 AF XY: 0.000143 AC XY: 104AN XY: 726418
GnomAD4 genome AF: 0.0000856 AC: 13AN: 151940Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74212
ClinVar
Submissions by phenotype
Merosin deficient congenital muscular dystrophy Uncertain:2
Uncertain significance, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Feb 16, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 02, 2018 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28554332) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 27, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 06, 2022 | Variant summary: LAMA2 c.715C>T (p.Arg239Cys) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 282172 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy (6.4e-05 vs 0.0022), allowing no conclusion about variant significance. c.715C>T has been reported in the literature in two homozygous siblings affected with moderate intellectual disability, seizures, ataxia, spastic diplegia and hypotonia (Bowling_2017). These phenotypes are consistent with Congenital Merosin Deficient Muscular Dystrophy (MIM # 607855). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and three as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
LAMA2-related muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the LAMA2 protein (p.Arg239Cys). This variant is present in population databases (rs145465528, gnomAD 0.01%). This missense change has been observed in individual(s) with developmental delays, seizures, ataxia, and spastic diplegia (PMID: 28554332). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224092). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 5). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (P) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD: p.(Arg239His): 7 heterozygotes, 0 homozygotes; p.(Arg239Leu): 1 heterozygote, 0 homozygotes. (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (laminin N-terminal domain; NCBI, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and homozygous in 2 affected siblings with intellectual disability, seizures, speech delay, ataxia and spastic diplegia (affected sibling also had hypertonia) (PMID: 28554332). This variant has also been reported as a variant with uncertain significance in ClinVar. (P) 0905 - No segregation evidence has been identified for this variant. There is no sufficient information for segregation evidence in the reported patients (PMID: 28554332). (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at