chr1-156137233-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_170707.4(LMNA):c.1608+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_170707.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1608+1G>A | splice_donor_variant, intron_variant | Intron 9 of 11 | ENST00000368300.9 | NP_733821.1 | ||
LMNA | NM_005572.4 | c.1608+1G>A | splice_donor_variant, intron_variant | Intron 9 of 9 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1608+1G>A | splice_donor_variant, intron_variant | Intron 9 of 11 | 1 | NM_170707.4 | ENSP00000357283.4 | |||
LMNA | ENST00000677389.1 | c.1608+1G>A | splice_donor_variant, intron_variant | Intron 9 of 9 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1A Pathogenic:2
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Some missense variants have been reported to result in a toxic gain of function or dominant negative effect and are associated with childhood-onset disease or skeletal muscle involvement, while other variants have been reported to result in a loss of function and haploinsufficiency, and are associated with adult-onset cardiac and myopathy disorders (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease. There are multiple phenotypes associated with this gene, however dilated cardiomyopathy type 1A (CMD1A) (MIM#115200) and Emery-Dreifuss muscular dystrophy 2 (MIM#181350; formerly limb-girdle muscular dystrophy type 1B (LGMD1B)) are inherited in a dominant manner (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. The majority of individuals published with this variant were diagnosed with LGMD1B, however a small number of cases were not reported with skeletal muscle involvement and considered to have CMD1A only. It has been suggested that individuals initially referred for DCM also be assessed for a history of mild muscle weakness (PMID: 19446900). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0701 - Other splice variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least four alternative variants, at the same nucleotide and in the surrounding splice region, have previously been reported in more than ten unrelated individuals with either LGMD1B or CMD1A (ClinVar, PMIDs: 24459210, 24915601, 29693488, 31744510, 33304817). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in at least eight probands, predominantly in association LGMD1B, however it has also been reported for CMD1A only (ClinVar, VCGS, PMIDs: 13129702, 15678000, 19446900, 31931689). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has previously been shown to segregation with disease in two LGMD1B families and one CMD1A family, in a total of seven affected genotyped individuals and two obligate carriers (VCGS, PMIDs: 15678000, 19446900, 31931689). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Experiments using transplanted heart tissue from an LGMD1B individual showed increased levels of phosphorylated ERK1/2 compared to controls, similar to the increased activity observed in in vitro and in vivo models of other pathogenic LMNA variants (PMID: 22068161). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Neuromuscular disease Pathogenic:1
The 1608+1G>A variant in LMNA gene was absent from large population studies but has been reported in one individual with limb-girdle muscular dystrophy type 1B (LGMD1B) with DCM and segregated with disease in 4 affected family members inclu ding 2 obligate carriers (Ambrosi 2009). It was also detected in 2 additional in dividuals with LGMD1B and conduction system disease as well as one affected fami ly member (Ben Yaou 2005). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing lea ding to an abnormal or absent protein. In summary, this variant meets our criter ia to be classified as pathogenic for LGMD1B in an autosomal dominant manner (ht tp://www.partners.org/personalizedmedicine/LMM) based upon segregation studies, absence from controls, predicted impact to the protein. -
Charcot-Marie-Tooth disease type 2 Pathogenic:1
This sequence change affects a donor splice site in intron 9 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant limb-girdle muscular dystrophy (PMID: 15678000, 19446900). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 66853). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The c.1608+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 of the LMNA gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, a significant portion of the protein is affected and the impacted region is critical for protein function (Ambry internal data). This variant (also referred to as IVS9+1G>A) has been detected in individuals with features consistent with laminopathies, including dilated cardiomyopathy, cardiac conduction disease, and limb-girdle muscular dystrophy, and has shown segregation with disease features in families (Ambrosi P et al. Int J Cardiol, 2009 Nov;137:e75-6; Ben Yaou R et al. Rev Neurol (Paris), 2005 Jan;161:42-54; Ramchand J et al. J Am Heart Assoc, 2020 Jan;9:e013346). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at