1-156138719-C-T

Variant names:

• chr1-156138719-C-T
• rs142000963
• NM_170707.4:c.1930C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_170707.4(LMNA):​c.1930C>T​(p.Arg644Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,613,372 control chromosomes in the GnomAD database, including 13 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. R644H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (13 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:12 B:12 O:1
• Conservation: PhyloP100: 3.06
• Publications: 78 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.063878536).
• BP6: Variant 1-156138719-C-T is Benign according to our data. Variant chr1-156138719-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14527.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (174/152150) while in subpopulation NFE AF = 0.0019 (129/67980). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1930C>T	p.Arg644Cys	missense_variant	Exon 11 of 12	ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1930C>T	p.Arg644Cys	missense_variant	Exon 11 of 12	1	NM_170707.4	ENSP00000357283.4

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00119 AC: 295 AN: 248536 AF XY: 0.00135

Gnomad AFR exome AF: 0.000504

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00197

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00210 AC: 3073 AN: 1461222 Hom.: 13 Cov.: 32 AF XY: 0.00209 AC XY: 1519 AN XY: 726932

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00153 AC: 132 AN: 86254

European-Finnish (FIN) AF: 0.000265 AC: 14 AN: 52798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00251 AC: 2793 AN: 1111996

Other (OTH) AF: 0.00169 AC: 102 AN: 60380

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74392

African (AFR) AF: 0.000723 AC: 30 AN: 41502

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 67980

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00162 Hom.: 2

Bravo AF: 0.00110

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00121 AC: 147

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:12 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:4

Mar 30, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg644Cys variant in LMNA has been detected by our laboratory in 7 individuals with cardiomyopathy (2 with DCM, 1 with LVNC, 2 with HCM, 1 with an unspecified cardiomyopathy, and 1 with VFib and a T-wave inversion). Four of these patients had a very early age at onset (range birth to 7 years) and no family history, which is atypical for LMNA variants. The p.Arg644Cys variant has also been identified in a large number of individuals (>20) with a diverse range of clinical features consistent with laminopathy, isolated cardiomyopathy (DCM, ARVC, HCM) or Hallermann-Streiff syndrome, a rare genetic disorder with clinical overlap with some laminopathies (Speckman 2000 PMID: 10739751, Genschel 2001 PMID: 11180602, Csoka 2004 PMID: 15060110, Mercuri 2005 PMID: 15770669, Muntoni 2006 PMID: 16585054, Rankin 2008 PMID: 18478590, Pasotti 2008 PMID: 18926329, Perrot 2009 PMID: 18795223, Møller 2009 PMID: 19875404, Kortum 2011 PMID: 22570643, Scharner 2011 PMID: 20848652, Larsen 2012 PMID: 22177269, Quarta 2012 PMID: 22199124, Vasli 2012 PMID: 22526018, Hoyer 2014 PMID: 25025039). In addition, one study reported non-segregation with disease in 2 families (Mercuri 2005 PMID: PMID: 15770669). This variant has also been identified in 0.2% (251/126914) of European chromosomes, including 1 homozygote, chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein; however, in vitro functional studies indicate the variant may affect nuclear morphology (Csoka 2004 PMID: 15060110). In summary, the lack of segregation with disease, its population frequency, and the wide-spectrum of observed phenotypes sugests that the p.Arg644Cys variant is likely benign. ACMG/AMP Criteria applied: BS1, BS4. -

Mar 31, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R644C variant of uncertain significance in the LMNA gene has been reported multiple times in association with LMNA-related disorders, and demonstrates a wide phenotypic spectrum, variable severity, incomplete penetrance, and non-segregation (Genschel et al., 2001; Csoka et al., 2004; Mercuri et al., 2005; Muntoni et al., 2006; Rankin et al., 2008; Pasotti et al., 2008; Moller et al., 2009; Perrot et al., 2009; Scharner et al., 2011; Quarta et al., 2012; Vasli et al., 2012; Larsen et al., 2012; Hoyer et al., 2014; Cann et al., 2016). The R644C variant has been identified in individuals with isolated cardiomyopathy, laminopathies, Hallermann-Streiff syndrome, or Hutchinson-Gilford progeria syndrome, and also in asymptomatic relatives. Additionally, two studies reported that the R644C variant did not segregate with disease in two unrelated families (Mercuri et al., 2005; Muntoni et al., 2006). The Exome Aggregation Consortium (ExAC) reports R644C was observed in 106/63,724 alleles from individuals of Non-Finnish European and 27/16,410 alleles from individuals of South Asian ancestry, including one homozygote, indicating it may be a rare benign variant in these populations (Lek et al., 2016). It has been suggested that the extreme phenotypic variability caused by this pleiotropic LMNA variant could be due to either an altered methylation pattern or abnormal post-translational processing of prelamin A because R644C is located at the C-terminal end of lamin A/C close to the endoproteolytic cleavage site (Perrot et al., 2009; Capell et al., 2006). The R644C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

not provided Uncertain:2 Benign:2 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 03, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Oct 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LMNA c.1930C>T; p.Arg644Cys variant (rs142000963) is reported in the literature in individuals affected with cardiomyopathy and laminopathy LMNA-related disorders, including variable phenotypes, severity, penetrance, and segregation (Mercuri 2005, Muntoni 2006, Rankin 2008, Seidelmann 2017, Stehlikova 2017). Additionally, a large pedigree with several affected family members were reported to carry p.Arg644Cys but the variant did not fully segregate with disease; these authors later identified an additional LMNA splicing variant that segregated in all affected family members who were tested (Sedaghat-Hamedani 2022). The p.Arg644Cys variant is reported in ClinVar (Variation ID: 14527), and is found in the general population with an overall allele frequency of 0.12% (334/279890 alleles, including a single homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.608). In vitro functional analyses of the variant protein show no significant effect on gap junctions or nuclear lamina integrity (De Vos 2011, Sun 2010), but other studies demonstrated impaired cleavage of lamin A (Barrowman 2012) and nuclear aberrations (Csoka 2004). While the high population frequency and lack of segregation with disease suggest that this is likely a benign variant, given the conflicting clinical and functional data, the significance of the p.Arg644Cys variant is uncertain at this time. References: Barrowman J et al. Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24. PLoS One. 2012;7(2):e32120. PMID: 22355414. Csoka AB et al. Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes. J Med Genet. 2004 Apr;41(4):304-8. PMID: 15060110. De Vos WH et al. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum Mol Genet. 2011 Nov 1;20(21):4175-86. PMID: 21831885. Mercuri E et al. Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene. Muscle Nerve. 2005 May;31(5):602-9. PMID: 15770669. Muntoni F et al. Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins. Brain. 2006 May;129(Pt 5):1260-8. PMID: 16585054. Rankin J et al. Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C. Am J Med Genet A. 2008 Jun 15;146A(12):1530-42. PMID: 18478590. Sedaghat-Hamedani F et al. Genotype Complements the Phenotype: Identification of the Pathogenicity of an LMNA Splice Variant by Nanopore Long-Read Sequencing in a Large DCM Family. Int J Mol Sci. 2022 Oct 13;23(20):12230. PMID: 36293084. Seidelmann SB et al. Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. Circ Cardiovasc Genet. 2017 Feb;10(1):e001573. PMID: 28087566. Stehlikova K et al. Muscular dystrophies and myopathies: the spectrum of mutated genes in the Czech Republic. Clin Genet. 2017 Mar;91(3):463-469. PMID: 27447704. Sun LP et al. Connexin 43 remodeling induced by LMNA gene mutation Glu82Lys in familial dilated cardiomyopathy with atrial ventricular block. Chin Med J (Engl). 2010 Apr 20;123(8):1058-62. PMID: 20497714. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMNA: BS2 -

Charcot-Marie-Tooth disease Pathogenic:1 Uncertain:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2013

Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Observed in two induviduals from two different families. -

Dilated cardiomyopathy 1A Uncertain:2

May 09, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5. -

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Uncertain:1 Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:2

Sep 12, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Variant of unknown significance Uncertain:1

Nov 01, 2009

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

LMNA-related disorder Uncertain:1

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LMNA c.1930C>T variant is predicted to result in the amino acid substitution p.Arg644Cys. The p.Arg644Cys variant has been identified in many unrelated individuals in association with different types of laminopathies, suggesting variable expressivity and incomplete penetrance (Rankin et al. 2008. PubMedID: 18478590). The phenotypic spectrum includes Emery-Dreifuss muscular dystrophy (Mercuri et al. 2005. PubMedID: 15770669), dilated cardiomyopathy (Genschel et al. 2001. PubMedID: 11180602; Parent et al. 2015. PubMedID: 25873806), and one patient with atypical progeria syndrome (Csoka et al. 2004. PubMedID: 15060110). However, the segregation data for the p.Arg644Cys variant is not conclusive (Mercuri et al. 2005. PubMedID: 15770669; Muntoni et al. 2006. PubMedID: 16585054). One study indicated that fibroblasts with the the p.Arg644Cys variant displayed normal nuclear morphology (van Tienen. 2019. PubMed ID: 30420677). This variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 1 homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial partial lipodystrophy, Dunnigan type Uncertain:1

Mar 20, 2023

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMNA NM_170707.3 exon 11 p.Arg644Cys (c.1930C>T): This variant has been reported in the literature in several individuals with a wide spectrum of laminopathy phenotypes, including cardiomyopathies, cardioskeletal myopathies, atypical progeria, lipodystrophy, neuropathy, arthrogryposis, and hepatic stenosis (Genschel 2000 PMID:11180602, Csoka 2004 PMID:15060110, Mercuri 2005 PMID:15770669, Passotti 2008 PMID:18926329, Rankin 2008 PMID:18478590, Perrot 2009 PMID:18795223, Scharner 2011 PMID:20848652, Kortum 2011 PMID:22570643, De Vos 2011 PMID:21831885, Larsen 2012 PMID:22177269, Quarta 2013 PMID:22199124, Hoyer 2014 PMID:25025039, Parent 2015 PMID:25873806, Stehlikova 2017 PMID:27447704). This variant segregated with disease in at least 3 individuals, but did not segregate with disease in at least two others (Mercuri 2005 PMID:15770669, Parent 2015 PMID:25873806). This variant was also present in several asymptomatic relatives, indicating that it may have reduced penetrance. However, this variant is also present in 0.1% (251/126914) of European alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/1-156108510-C-T), suggesting that it may be a common benign variant. This variant is present in ClinVar with conflicting interpretations (Variation ID:14527). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies have demonstrated partial inhibition of ZMPSTE24 cleavage with this variant (Barrowman 2012 PMID:22355414). However, multiple expression studies in fibroblast cultures of individuals with this variant have shown no effect on gap junctions and normal nuclear morphology (Sun 2010 PMID:20497714, De Vos 2011 PMID:21831885, van Tienen 2019 PMID:30420677). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Monogenic diabetes Benign:1

Nov 02, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BS4 (lack of segregation in 15770669, 16585054), BS1 (0.2% MAF in EurNF), BS2 (two homozygotes in gnomAD), PS3 (reduces cleavage efficacy of prelaminA tail: 28663758, 22355414) [REVEL 0.608, PP3 (8), BP4 (2) = conflicting evidence, not using] = Benign -

Charcot-Marie-Tooth disease type 2 Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Nov 05, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	.;T;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.064	T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.81	.;L;.;.;.
PhyloP100		3.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.56	N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.81
MVP		0.96
MPC		0.96
ClinPred		0.045	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.75
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs142000963; hg19: chr1-156108510; COSMIC: COSV61542409; COSMIC: COSV61542409;