1-156135894-C-G

Position:

• chr1-156135894-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_170707.4(LMNA):​c.937-7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,612,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: LMNA NM_170707.4 splice_region, intron
• Scores: Splicing: ADA: 0.002806
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3 O:1
• Conservation: PhyloP100: 1.10

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

LMNA (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.937-7C>G		splice_region_variant, intron_variant		ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.937-7C>G		splice_region_variant, intron_variant		ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.937-7C>G		splice_region_variant, intron_variant		1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.937-7C>G		splice_region_variant, intron_variant			NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152220 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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000325 AC: 8 AN: 246476 Hom.: 0 AF XY: 0.0000373 AC XY: 5 AN XY: 134194

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.0000361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1460740 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 726648

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

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: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1 Other:1

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	Reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare variants in the Exome Aggregation Consortium (Ito et al., 2017); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32376792, 18796515, 28679633) -

Primary dilated cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2019	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is an intronic variant. It is not predicted to affect splicing but an in vitro study shows that the variant has an effect on splicing (Ito 2017). Clinvar: LB (GeneDx), VUS (Invitae). Gnomad: 0.012% (4 alleles). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 10, 2024	This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2022	Variant summary: LMNA c.937-7C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site, whereas one predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing, impacting approximately 55% of all transcripts, with 45% exhibiting normal splicing (e.g. Ito_2017). The variant allele was found at a frequency of 3.6e-05 in 277870 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (3.6e-05 vs 0.0001), allowing no conclusion about variant significance. c.937-7C>G has been reported in the literature in a setting of multi-gene panel testing as a VUS in one individual affected with Dilated Cardiomyopathy (e.g. Lakdawala_2012). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 20, 2023

This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change falls in intron 5 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs267607681, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 22464770, 28679633, 32376792). ClinVar contains an entry for this variant (Variation ID: 66959). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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. -

Dilated cardiomyopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 11, 2024

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Missense variants have been reported to result in gain-of-function, as well as dominant-negative, and are associated to a more severe and earlier phenotype. Truncating variants have been shown to result in loss-of-function associated with a milder and later-onset disease (PMID: 17377071). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance. Emery-Dreifuss muscular dystrophy has been reported to have incomplete penetrance (PMID: 20301609). (N) 0212 - Non-canonical splice variant without proven consequence on splicing (intron 5). RNA studies previously performed at VCGS with this proband’s mother sample were inconclusive. (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a dominant or recessive condition (10 heterozygotes, 0 homozygotes). (P) 0309 - Multiple alternative nucleotide changes at the same position have been observed in gnomAD (highest allele count: 1 heterozygote, 0 homozygotes). (N) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. However, this variant might enhance abnormal use of an available cryptic 3’ splice site (personal communication). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as part of a haplotype in a patient with severe mandibuloacral dysplasia and it has also been found in patients with dilated cardiomyopathy (ClinVar; LOVD; PMID: 18796515; PMID: 28679633). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant alone. However, functional studies showing impact in protein function were performed using fibroblasts from a patient with a haplotype containing this variant along with others (PMID: 18796515). Therefore, it is not possible to determine which of the variants within the haplotype is functional. (N) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.1
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0028
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -33

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607681; hg19: chr1-156105685;