1-156135894-C-G

Variant names:

• chr1-156135894-C-G
• rs267607681
• NM_170707.4:c.937-7C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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:9 B:3 O:1
• Conservation: PhyloP100: 1.10
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• familial partial lipodystrophy, Dunnigan type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• restrictive dermopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• Emery-Dreifuss muscular dystrophy 2, autosomal dominant

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• atrioventricular block

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• heart-hand syndrome, Slovenian type

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• Charcot-Marie-Tooth disease type 2B1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 3, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mandibuloacral dysplasia with type A lipodystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• atrial fibrillation

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• atypical Werner syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy due to LMNA mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal restrictive dermopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LMNA-related cardiocutaneous progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Emery-Dreifuss muscular dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal semi-dominant severe lipodystrophic laminopathy

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.937-7C>G		splice_region_variant, intron_variant	Intron 5 of 11	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.937-7C>G		splice_region_variant, intron_variant	Intron 5 of 9	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.937-7C>G		splice_region_variant, intron_variant	Intron 5 of 11	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.937-7C>G		splice_region_variant, intron_variant	Intron 5 of 9		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

GnomAD2 exomes AF: 0.0000325 AC: 8 AN: 246476 AF XY: 0.0000373

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 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

African (AFR) AF: 0.000120 AC: 4 AN: 33464

American (AMR) AF: 0.000112 AC: 5 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52756

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111676

Other (OTH) AF: 0.0000497 AC: 3 AN: 60354

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

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1 Other:1

Mar 18, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 28679633); Reported previously as a variant of uncertain significance in a patient with suspected Charcot-Marie-Tooth disease; however, no further clinical or segregation information was provided (PMID: 32376792); 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: 28679633, 34461741, 35470680, 22464770, 18796515, 32376792) -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 07, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Uncertain:2

Apr 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 14, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 causes 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

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;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;C5979868:Dilated cardiomyopathy 1A Uncertain:1

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.1
DANN	Benign	0.33
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs267607681; hg19: chr1-156105685;