VCV000004271.53 - ClinVar

NM_005857.5(ZMPSTE24):c.1085dup (p.Leu362fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(20)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005857.5(ZMPSTE24):c.1085dup (p.Leu362fs)

Variation ID: 4271 Accession: VCV000004271.53

Type and length

Duplication, 1 bp

Location

Cytogenetic: 1p34.2 1: 40290870-40290871 (GRCh38) [ NCBI UCSC ] 1: 40756542-40756543 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 23, 2014	Nov 24, 2024	Nov 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005857.5:c.1076_1077insT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_005857.5:c.1085dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005848.2:p.Leu362fs	frameshift
NM_005857.3:c.1077dupT
NM_005857.4:c.1085dupT
NC_000001.11:g.40290879dup
NC_000001.10:g.40756551dup
NG_008695.1:g.37819dup
LRG_212:g.37819dup
LRG_212t1:c.1085dup	LRG_212p1:p.Leu362Phefs

... more HGVS ... less HGVS

Protein change

L362fs

Other names

Canonical SPDI

NC_000001.11:40290870:TTTTTTTTT:TTTTTTTTTT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA116749 OMIM: 606480.0001 dbSNP: rs137854889 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ZMPSTE24		-	-	GRCh38 GRCh37	199	238

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mandibuloacral dysplasia with type B lipodystrophy	Pathogenic (2)	criteria provided, single submitter	Jul 22, 2022	RCV000004492.8
Lethal tight skin contracture syndrome	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 1, 2023	RCV000023547.15
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Nov 12, 2023	RCV000128723.37
ZMPSTE24-related disorder	Pathogenic (1)	criteria provided, single submitter	Oct 13, 2017	RCV000335839.7
Lethal tight skin contracture syndrome Mandibuloacral dysplasia with type B lipodystrophy	Pathogenic (1)	criteria provided, single submitter	Jan 10, 2022	RCV002490308.2
Restrictive dermopathy 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV004593959.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 31, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000746681.2 First in ClinVar: Apr 29, 2018 Last updated: Jun 04, 2018	Comment: A mosaic c.1077dupT (p.L362fs) pathogenic variant in the ZMPSTE24 gene was detected in this individual. The c.1077dupT change predicts a translation frameshift at residue 362 … (more) A mosaic c.1077dupT (p.L362fs) pathogenic variant in the ZMPSTE24 gene was detected in this individual. The c.1077dupT change predicts a translation frameshift at residue 362 with subsequent premature translation termination. This variant has been previously reported as disease causing [aka c.1085dupT (p.Phe361fsX379); PMID 12913070, 22718200, 19442658, 21831885, 22495976, 25629449, 19020898].Whole exome sequencing detected both the reference G allele and the variant GT allele at cDNA position 1077 in this patient. The exome sequencing data showed an increased number of the variant reads (n=98) compared to the reference reads (n=20), suggesting mosaicism for this change in the patient. This individual has been reported in PMID: 29341437. (less) Number of individuals with the variant: 1 Clinical Features: Ventriculomegaly (present) , Preeclampsia (present) , Tibial torsion (present) , Thoracic scoliosis (present) , Sparse scalp hair (present) , Small hand (present) , Small for … (more) Ventriculomegaly (present) , Preeclampsia (present) , Tibial torsion (present) , Thoracic scoliosis (present) , Sparse scalp hair (present) , Small hand (present) , Small for gestational age (present) , Short foot (present) , Relative macrocephaly (present) , Proportionate short stature (present) , Premature birth (present) , Poor suck (present) , Neonatal sepsis (present) , Neonatal respiratory distress (present) , Neonatal hypoglycemia (present) , Narrow nail (present) , Microtia (present) , Maternal hypertension (present) , Hypermetropia (present) , Hearing impairment (present) , Fragile skin (present) , Finger clinodactyly (present) , Downslanted palpebral fissures (present) , Dermal translucency (present) , Decreased fetal movement (present) , Congenital microcephaly (present) , Camptodactyly of finger (present) , Blepharophimosis (present) , Birth length less than 3rd percentile (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: White Comment on evidence: Our patient was mosaic for the ZMPSTE24 RV with 66% of her cells homoz and 34% heteroz for the L362fs. This mosaicsm lessened the severity … (more) Our patient was mosaic for the ZMPSTE24 RV with 66% of her cells homoz and 34% heteroz for the L362fs. This mosaicsm lessened the severity of the patient's phenotype. This patient has been reported in PMID:29341437 (less) Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2016-07-31 Testing laboratory interpretation: Pathogenic
Pathogenic (Dec 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital Muenster Accession: SCV002098362.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022	Comment: ACMG categories: PVS1,PM2,PM3,PP5 Number of individuals with the variant: 1 Age: 60-69 years Sex: male Tissue: blood
Pathogenic (Jan 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 Mandibuloacral dysplasia with type B lipodystrophy Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002777181.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003841253.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023	Publications: PubMed (3) PubMed: 22718200‚ 21108632‚ 24169522 Comment: A Heterozygous Frameshift variant c.1076_1077insT in Exon 9 of the ZMPSTE24 gene that results in the amino acid substitution p.Leu362fs19 was identified. The observed variant … (more) A Heterozygous Frameshift variant c.1076_1077insT in Exon 9 of the ZMPSTE24 gene that results in the amino acid substitution p.Leu362fs19 was identified. The observed variant has a maximum allele frequency of 0.00026% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 4271 as of 2023-01-21). This sequence change creates a premature translational stop signal (p.Leu362Phefs*19) in the ZMPSTE24 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZMPSTE24 are known to be pathogenic (Barrowman, Jemima et al., 2012). Additionally, mutations in the gene are associated with restrictive dermopathy and Mandibuloacral dysplasia (Ahmad, Z et al., 2012; Navarro, Claire Laure et al., 2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020941.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 13, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	ZMPSTE24-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000357433.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (7) PubMed: 21108632‚ 20034068‚ 16297189‚ 22718200‚ 15317753‚ 22495976‚ 12913070 Comment: The ZMPSTE24 c.1085dupT (p.Leu362PhefsTer19) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu362PhefsTer19 variant has been … (more) The ZMPSTE24 c.1085dupT (p.Leu362PhefsTer19) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu362PhefsTer19 variant has been reported in six studies in which it is found in a compound heterozygous state with a missense variant in one individual with mandibuloacral dysplasia (Agarwal et al. 2003) and in a total of 14 individuals with lethal restrictive dermopathy including in six in homozygous state, in one in a compound heterozygous state, and in seven in a heterozygous state (Navarro et al. 2004; Moulson et al. 2005; Li 2010; Loucks et al. 2012; Ahmad et al. 2012). The p.Leu362PhefsTer19 variant was absent from over 500 control chromosomes and is reported at a frequency of 0.00062 in the South Asian population of the Exome Aggregation Consortium. Yeast complementation assays demonstrated that the p.Leu362PhefsTer19 variant protein, unlike wild type, was unable to rescue a growth arrest phenotype and results in only 1% of the wild type protein activity (Barrowman et al. 2012). The variant was also shown to result in a defect in prelamin A processing (Moulson et al. 2005). Based on the collective evidence and the potential impact of frameshift variants, the p.Leu362PhefsTer19 variant is classified as pathogenic for ZMPSTE24-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Aug 31, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001168548.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Comment: The c.1085dupT variant in the ZMPSTE24 gene has been reported previously in association with restrictive dermopathy when present in the homozygous state (Loucks et al., … (more) The c.1085dupT variant in the ZMPSTE24 gene has been reported previously in association with restrictive dermopathy when present in the homozygous state (Loucks et al., 2012; Dutta and Danda, 2016; De Vos et al., 2011). The c.1085dupT variant causes a frameshift starting with codon Leucine 362, changes this amino acid to a Phenylalanine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Leu362PhefsX19. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies showed no proteolytic activity for the c.1085dupT variant (Barrowman et al., 2012).The c.1085dupT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1085dupT as a pathogenic variant. (less)
Pathogenic (Aug 11, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001950007.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Comment: This variant was identified as compound heterozygous with NM_005857.5:c.50del.
Pathogenic (Jul 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mandibuloacral dysplasia with type B lipodystrophy Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835263.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004175753.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: The frameshift c.1085dup (p.Leu362PhefsTer19) variant in ZMPSTE24 gene has been previously reported in homozygous, heterozygous and compound heterozygous states in multiple individuals affected with Restrictive … (more) The frameshift c.1085dup (p.Leu362PhefsTer19) variant in ZMPSTE24 gene has been previously reported in homozygous, heterozygous and compound heterozygous states in multiple individuals affected with Restrictive Dermatopathy (Li, 2010; Ahmad et al., 2012; Moulson et al., 2005). The p.Leu362PhefsTer19 variant has been reported with allele frequency of 0.03% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Leucine 362, changes this amino acid to Phenylalanine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Leu362PhefsTer19. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 12, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001215302.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 22718200‚ 24169522‚ 12913070‚ 19020898‚ 21831885‚ 22495976‚ 25629449 Comment: This sequence change creates a premature translational stop signal (p.Leu362Phefs19) in the ZMPSTE24 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu362Phefs19) in the ZMPSTE24 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZMPSTE24 are known to be pathogenic (PMID: 22718200, 24169522). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mandibuloacral dysplasia or restrictive dermopathy (PMID: 12913070, 19020898, 21831885, 22495976, 25629449). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4271). 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. (less)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005087231.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 22718200‚ 24169522 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mandibuloacral dysplasia with type B lipodystrophy, (MAD-B; MIM#608612) and restrictive dermopathy 1, (RD; MIM#275210). (I) 0106 - This gene is associated with autosomal recessive disease. Variants that result in residual protein function lead to MAD-B, while complete loss-of-function alleles lead to RD (PMID: 22718200). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 93 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common pathogenic variants reported in MAD-B and RD individuals, depending on their second allele (PMID: 24169522, ClinVar). (SP) 1102 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jul 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247435.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Jun 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive dermopathy 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005401020.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: The observed frameshift c.1085dup(p.Leu362PhefsTer19) variant in ZMPSTE24 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with restrictive dermopathy … (more) The observed frameshift c.1085dup(p.Leu362PhefsTer19) variant in ZMPSTE24 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with restrictive dermopathy (Kwan JM., 2015; Navarro CL, et al., 2014; Loucks C, et al., 2012; Ahmad Z, et al., 2012). This variant has also been observed to segregate with disease in related individuals. This variant has been reported to be a common founder variant in Old Colony Mennonite (OCM) and Hutterites (Loucks C, et al., 2012). The p.Leu362PhefsTer19 variant is present with allele frequency of 0.03% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Leucine 362, changes this amino acid to Phenylalanine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Leu362PhefsTer19. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in ZMPSTE24 gene have been previously reported to be disease causing (Navarro CL, et al., 2014; Barrowman J, et al., 2012). For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the skin (present)
Pathogenic (May 01, 2012)	no assertion criteria provided Method: literature only	RESTRICTIVE DERMOPATHY, LETHAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044838.4 First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018	Publications: PubMed (8) PubMed: 12913070‚ 15317753‚ 16297189‚ 20034068‚ 20635340‚ 22495976‚ 8152880‚ 3840649 Comment on evidence: In a Belgian woman with mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy (MADB; 608612), Agarwal et al. (2003) identified compound heterozygosity for a 1-bp duplication … (more) In a Belgian woman with mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy (MADB; 608612), Agarwal et al. (2003) identified compound heterozygosity for a 1-bp duplication (1085dupT) in exon 9 of the ZMPSTE24 gene, resulting in a frameshift and a truncated protein (Phe361fsTer379), and a missense mutation (606480.0002). Neither mutation was found among 100 control subjects. Navarro et al. (2004) identified a heterozygous 1085dupT mutation 7 unrelated infants with lethal restrictive dermopathy (275210). The mutation was predicted to result in a frameshift and a premature stop codon 18 codons downstream. Loss of expression of lamin A (LMNA; 150330), abnormal patterns of nuclear sizes and shapes, and mislocalization of lamin-associated proteins was seen in fibroblasts from these patients. Moulson et al. (2005) hypothesized that the patients reported by Navarro et al. (2004) with heterozygous mutations actually had a second pathogenic mutation in the ZMPSTE24 gene that was not detected. Moulson et al. (2005) identified a homozygous 1085dupT mutation in a Dutch patient and in a American patient of German origin, both with restrictive dermopathy. The Dutch patient was born of consanguineous parents. Fibroblasts derived from a patient who was homozygous for the mutation showed that LMNA was distributed in clusters in the nucleus, which was different from the uniform distribution of LMNA in nuclei of control fibroblasts. These findings indicated that the disorder results from a specific defect in LMNA processing. Another unrelated Dutch patient with restrictive dermopathy disorder was compound heterozygous for 2 mutations: 1085dupT and 591dupT (606480.0008). Li (2010) identified a homozygous 1085dupT mutation in an infant girl with restrictive dermopathy. She was born of Mexican Mennonite parents who had immigrated to Canada. The mother reported several neonatal deaths in her family. Li (2010) postulated that since this family was of Mennonite descent, it may represent a founder mutation in this group. However, Miner (2010) noted that Moulson et al. (2005) had previously identified a different truncating mutation in the ZMPSTE24 gene (54dupT; 606480.0007) as causing restrictive dermopathy in 2 related Mennonite families from Pennsylvania, suggesting allelic heterogeneity even within this isolated population. In 2 unrelated Old Colony Mennonite infants, 1 from Alberta and 1 from Ontario, who died shortly after birth from restrictive dermopathy, Loucks et al. (2012) identified homozygosity for the common 1085dupT mutation in the ZMPSTE24 gene. In addition, the mutation was found in heterozygosity in the obligate-carrier parents of 2 unrelated deceased Schmiedeleut Hutterite infants with restrictive dermopathy, 1 from South Dakota and 1 from Manitoba (the latter patient was originally reported by Reed et al., 1993). Haplotype analysis suggested a small 1.36-Mb shared haplotype distal to the mutation. In a cohort of approximately 1,200 Schmiedeleut Hutterites from South Dakota, Loucks et al. (2012) determined a high carrier frequency of the 1085dupT mutation (approximately 1/21), making it likely that the mutation predates the 1874 separation of the Hutterites into the 3 current essentially endogamous leuts and lending support to the hypothesis (Lowry et al., 1985) that the mutation was introduced into the Hutterites in 1783 when some Mennonites joined the Hutterite brethren. Noting that the 1085dupT mutation accounts for nearly 75% of the reported causative ZMPSTE24 mutations in restrictive dermopathy mutations, Loucks et al. (2012) suggested that 1085dupT may represent a recurrent mutation due to a mutational hotspot. (less)
Pathogenic (May 01, 2012)	no assertion criteria provided Method: literature only	MANDIBULOACRAL DYSPLASIA WITH TYPE B LIPODYSTROPHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024666.4 First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018	Publications: PubMed (8) PubMed: 12913070‚ 15317753‚ 16297189‚ 20034068‚ 20635340‚ 22495976‚ 8152880‚ 3840649 Comment on evidence: In a Belgian woman with mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy (MADB; 608612), Agarwal et al. (2003) identified compound heterozygosity for a 1-bp duplication … (more) In a Belgian woman with mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy (MADB; 608612), Agarwal et al. (2003) identified compound heterozygosity for a 1-bp duplication (1085dupT) in exon 9 of the ZMPSTE24 gene, resulting in a frameshift and a truncated protein (Phe361fsTer379), and a missense mutation (606480.0002). Neither mutation was found among 100 control subjects. Navarro et al. (2004) identified a heterozygous 1085dupT mutation 7 unrelated infants with lethal restrictive dermopathy (275210). The mutation was predicted to result in a frameshift and a premature stop codon 18 codons downstream. Loss of expression of lamin A (LMNA; 150330), abnormal patterns of nuclear sizes and shapes, and mislocalization of lamin-associated proteins was seen in fibroblasts from these patients. Moulson et al. (2005) hypothesized that the patients reported by Navarro et al. (2004) with heterozygous mutations actually had a second pathogenic mutation in the ZMPSTE24 gene that was not detected. Moulson et al. (2005) identified a homozygous 1085dupT mutation in a Dutch patient and in a American patient of German origin, both with restrictive dermopathy. The Dutch patient was born of consanguineous parents. Fibroblasts derived from a patient who was homozygous for the mutation showed that LMNA was distributed in clusters in the nucleus, which was different from the uniform distribution of LMNA in nuclei of control fibroblasts. These findings indicated that the disorder results from a specific defect in LMNA processing. Another unrelated Dutch patient with restrictive dermopathy disorder was compound heterozygous for 2 mutations: 1085dupT and 591dupT (606480.0008). Li (2010) identified a homozygous 1085dupT mutation in an infant girl with restrictive dermopathy. She was born of Mexican Mennonite parents who had immigrated to Canada. The mother reported several neonatal deaths in her family. Li (2010) postulated that since this family was of Mennonite descent, it may represent a founder mutation in this group. However, Miner (2010) noted that Moulson et al. (2005) had previously identified a different truncating mutation in the ZMPSTE24 gene (54dupT; 606480.0007) as causing restrictive dermopathy in 2 related Mennonite families from Pennsylvania, suggesting allelic heterogeneity even within this isolated population. In 2 unrelated Old Colony Mennonite infants, 1 from Alberta and 1 from Ontario, who died shortly after birth from restrictive dermopathy, Loucks et al. (2012) identified homozygosity for the common 1085dupT mutation in the ZMPSTE24 gene. In addition, the mutation was found in heterozygosity in the obligate-carrier parents of 2 unrelated deceased Schmiedeleut Hutterite infants with restrictive dermopathy, 1 from South Dakota and 1 from Manitoba (the latter patient was originally reported by Reed et al., 1993). Haplotype analysis suggested a small 1.36-Mb shared haplotype distal to the mutation. In a cohort of approximately 1,200 Schmiedeleut Hutterites from South Dakota, Loucks et al. (2012) determined a high carrier frequency of the 1085dupT mutation (approximately 1/21), making it likely that the mutation predates the 1874 separation of the Hutterites into the 3 current essentially endogamous leuts and lending support to the hypothesis (Lowry et al., 1985) that the mutation was introduced into the Hutterites in 1783 when some Mennonites joined the Hutterite brethren. Noting that the 1085dupT mutation accounts for nearly 75% of the reported causative ZMPSTE24 mutations in restrictive dermopathy mutations, Loucks et al. (2012) suggested that 1085dupT may represent a recurrent mutation due to a mutational hotspot. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798019.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001962865.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034106.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: germline	ZMPSTE24 homepage - Leiden Muscular Dystrophy pages Accession: SCV000172363.1 First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014 Comment: has functional consequence
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Comment:

A mosaic c.1077dupT (p.L362fs) pathogenic variant in the ZMPSTE24 gene was detected in this individual. The c.1077dupT change predicts a translation frameshift at residue 362 with subsequent premature translation termination. This variant has been previously reported as disease causing [aka c.1085dupT (p.Phe361fsX379); PMID 12913070, 22718200, 19442658, 21831885, 22495976, 25629449, 19020898].Whole exome sequencing detected both the reference G allele and the variant GT allele at cDNA position 1077 in this patient. The exome sequencing data showed an increased number of the variant reads (n=98) compared to the reference reads (n=20), suggesting mosaicism for this change in the patient. This individual has been reported in PMID: 29341437.

Comment:

A Heterozygous Frameshift variant c.1076_1077insT in Exon 9 of the ZMPSTE24 gene that results in the amino acid substitution p.Leu362fs*19 was identified. The observed variant has a maximum allele frequency of 0.00026% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 4271 as of 2023-01-21). This sequence change creates a premature translational stop signal (p.Leu362Phefs*19) in the ZMPSTE24 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZMPSTE24 are known to be pathogenic (Barrowman, Jemima et al., 2012). Additionally, mutations in the gene are associated with restrictive dermopathy and Mandibuloacral dysplasia (Ahmad, Z et al., 2012; Navarro, Claire Laure et al., 2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Comment:

The ZMPSTE24 c.1085dupT (p.Leu362PhefsTer19) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu362PhefsTer19 variant has been reported in six studies in which it is found in a compound heterozygous state with a missense variant in one individual with mandibuloacral dysplasia (Agarwal et al. 2003) and in a total of 14 individuals with lethal restrictive dermopathy including in six in homozygous state, in one in a compound heterozygous state, and in seven in a heterozygous state (Navarro et al. 2004; Moulson et al. 2005; Li 2010; Loucks et al. 2012; Ahmad et al. 2012). The p.Leu362PhefsTer19 variant was absent from over 500 control chromosomes and is reported at a frequency of 0.00062 in the South Asian population of the Exome Aggregation Consortium. Yeast complementation assays demonstrated that the p.Leu362PhefsTer19 variant protein, unlike wild type, was unable to rescue a growth arrest phenotype and results in only 1% of the wild type protein activity (Barrowman et al. 2012). The variant was also shown to result in a defect in prelamin A processing (Moulson et al. 2005). Based on the collective evidence and the potential impact of frameshift variants, the p.Leu362PhefsTer19 variant is classified as pathogenic for ZMPSTE24-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The c.1085dupT variant in the ZMPSTE24 gene has been reported previously in association with restrictive dermopathy when present in the homozygous state (Loucks et al., 2012; Dutta and Danda, 2016; De Vos et al., 2011). The c.1085dupT variant causes a frameshift starting with codon Leucine 362, changes this amino acid to a Phenylalanine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Leu362PhefsX19. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies showed no proteolytic activity for the c.1085dupT variant (Barrowman et al., 2012).The c.1085dupT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1085dupT as a pathogenic variant.

Comment:

The frameshift c.1085dup (p.Leu362PhefsTer19) variant in ZMPSTE24 gene has been previously reported in homozygous, heterozygous and compound heterozygous states in multiple individuals affected with Restrictive Dermatopathy (Li, 2010; Ahmad et al., 2012; Moulson et al., 2005). The p.Leu362PhefsTer19 variant has been reported with allele frequency of 0.03% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Leucine 362, changes this amino acid to Phenylalanine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Leu362PhefsTer19. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Leu362Phefs*19) in the ZMPSTE24 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZMPSTE24 are known to be pathogenic (PMID: 22718200, 24169522). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mandibuloacral dysplasia or restrictive dermopathy (PMID: 12913070, 19020898, 21831885, 22495976, 25629449). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4271). 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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mandibuloacral dysplasia with type B lipodystrophy, (MAD-B; MIM#608612) and restrictive dermopathy 1, (RD; MIM#275210). (I) 0106 - This gene is associated with autosomal recessive disease. Variants that result in residual protein function lead to MAD-B, while complete loss-of-function alleles lead to RD (PMID: 22718200). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 93 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common pathogenic variants reported in MAD-B and RD individuals, depending on their second allele (PMID: 24169522, ClinVar). (SP) 1102 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The observed frameshift c.1085dup(p.Leu362PhefsTer19) variant in ZMPSTE24 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with restrictive dermopathy (Kwan JM., 2015; Navarro CL, et al., 2014; Loucks C, et al., 2012; Ahmad Z, et al., 2012). This variant has also been observed to segregate with disease in related individuals. This variant has been reported to be a common founder variant in Old Colony Mennonite (OCM) and Hutterites (Loucks C, et al., 2012). The p.Leu362PhefsTer19 variant is present with allele frequency of 0.03% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Leucine 362, changes this amino acid to Phenylalanine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Leu362PhefsTer19. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in ZMPSTE24 gene have been previously reported to be disease causing (Navarro CL, et al., 2014; Barrowman J, et al., 2012). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mandibuloacral dysplasia type B in an infant: a rare progeroid genodermatosis.	Kwan JM	JAMA dermatology	2015	PMID: 25629449
New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update.	Navarro CL	European journal of human genetics : EJHG	2014	PMID: 24169522
Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity.	Barrowman J	Human molecular genetics	2012	PMID: 22718200
A shared founder mutation underlies restrictive dermopathy in Old Colony (Dutch-German) Mennonite and Hutterite patients in North America.	Loucks C	American journal of medical genetics. Part A	2012	PMID: 22495976
Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: evidence of genetic heterogeneity.	Ahmad Z	Clinical genetics	2012	PMID: 21108632
Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies.	De Vos WH	Human molecular genetics	2011	PMID: 21831885
Restrictive dermopathy and ZMPSTE24 mutations in Mennonites: Evidence for allelic heterogeneity.	Miner JH	American journal of medical genetics. Part A	2010	PMID: 20635340
Homozygosity for the common mutation c.1085dupT in the ZMPSTE24 gene in a Mennonite baby with restrictive dermopathy and placenta abruption.	Li C	American journal of medical genetics. Part A	2010	PMID: 20034068
Restrictive dermopathy--a lethal congenital laminopathy. Case report and review of the literature.	Morais P	European journal of pediatrics	2009	PMID: 19020898
Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy.	Moulson CL	The Journal of investigative dermatology	2005	PMID: 16297189
Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.	Navarro CL	Human molecular genetics	2004	PMID: 15317753
Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia.	Agarwal AK	Human molecular genetics	2003	PMID: 12913070
Restrictive dermopathy.	Reed MH	Pediatric radiology	1993	PMID: 8152880
Congenital contractures, edema, hyperkeratosis, and intrauterine growth retardation: a fatal syndrome in Hutterite and Mennonite kindreds.	Lowry RB	American journal of medical genetics	1985	PMID: 3840649
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Text-mined citations for rs137854889 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_005857.5(ZMPSTE24):c.1085dup (p.Leu362fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137854889 ...