VCV000126949.43 - ClinVar

NM_000428.3(LTBP2):c.1295C>T (p.Pro432Leu)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance (2); Benign (3); Likely benign (2)

7 out of 10 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000428.3(LTBP2):c.1295C>T (p.Pro432Leu)

Variation ID: 126949 Accession: VCV000126949.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.3 14: 74552291 (GRCh38) [ NCBI UCSC ] 14: 75018994 (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	Apr 24, 2014	Jun 20, 2026	Feb 2, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000428.3:c.1295C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000419.1:p.Pro432Leu	missense
NC_000014.9:g.74552291G>A
NC_000014.8:g.75018994G>A
NG_021486.1:g.65041C>T

Protein change

P432L

Other names

Canonical SPDI

NC_000014.9:74552290:G:A

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.

0.00220 (A)

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

The Genome Aggregation Database (gnomAD) 0.00032

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

Trans-Omics for Precision Medicine (TOPMed) 0.00085

The Genome Aggregation Database (gnomAD), exomes 0.00097

Exome Aggregation Consortium (ExAC) 0.00186

1000 Genomes Project 30x 0.00187

1000 Genomes Project 0.00220

Links

ClinGen: CA151335 dbSNP: rs137854861 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.
LTBP2		-	-	GRCh38 GRCh37	1714	1730

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.
Pseudoexfoliation glaucoma	Conflicting classifications of pathogenicity (2)	no assertion criteria provided	Jan 6, 2020	RCV000114805.6
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 2, 2026	RCV000971799.34
Weill-Marchesani syndrome	Benign (1)	criteria provided, single submitter	Apr 28, 2017	RCV001117710.4
Weill-Marchesani syndrome 3	Uncertain significance (1)	criteria provided, single submitter	May 28, 2019	RCV000989244.1
Glaucoma 3, primary congenital, D	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2017	RCV001117709.4
Glaucoma 3, primary congenital, D Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma Weill-Marchesani syndrome 3	Likely benign (1)	criteria provided, single submitter	-	RCV003224148.2
LTBP2-related disorder	Likely benign (1)	no assertion criteria provided	Jun 19, 2024	RCV004734648.1

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.	Expand all rows Collapse all rows 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.
Uncertain significance (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Glaucoma 3, primary congenital, D	Illumina Laboratory Services, Illumina Accession: SCV001275927.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 23401661 Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Weill-Marchesani syndrome	Illumina Laboratory Services, Illumina Accession: SCV001275928.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Feb 21, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001837362.1 First in ClinVar: Sep 10, 2021 Last updated: Sep 10, 2021	Comment: show This variant is associated with the following publications: (PMID: 31589614, 27884173, 23401661) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (May 28, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Weill-Marchesani syndrome 3	Mendelics Accession: SCV001139486.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Glaucoma 3, primary congenital, D Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma Weill-Marchesani syndrome 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920167.2 First in ClinVar: Apr 30, 2023 Last updated: May 03, 2025	Comment: show This variant has been reported in the heterozygous state in one individual with primary open angle glaucoma and one with pseudoexfoliation syndrome (Jelodari-Mamaghani 2013 PMID:23401661). However, this variant is present in 0.8% (245/30610) of South Asian alleles in the Genome Aggregation Database, and in 1 homozygote in each of v2.1.1 and v3.1.2 (https://gnomad.broadinstitute.org/variant/14-75018994-G-A?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Feb 02, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001119467.7 First in ClinVar: Dec 17, 2019 Last updated: Mar 07, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jul 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV004136901.22 First in ClinVar: Nov 20, 2023 Last updated: Jun 20, 2026	Comment: show LTBP2: BP4, BS2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 4

Uncertain significance (Jan 06, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Pseudoexfoliation glaucoma	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142442.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Comment: show NM_000428.2:c.1295C>T in the LTBP2 gene has an allele frequency of 0.008 in South Asian subpopulation in the gnomAD database. The c.1295C>T (p.Pro432Leu) variant has been observed in a patient affected with pseudoexfoliation glaucoma (PEXG) syndrome (PMID: 23401661). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Pseudoexfoliation glaucoma	Elahi Laboratory, University of Tehran Accession: SCV000148700.2 First in ClinVar: Apr 24, 2014 Last updated: Jun 08, 2025	Comment: show Converted during submission from probable-pathogenic to Likely pathogenic. (less) Observation: 1 Collection method: not provided Allele origin: unknown Affected status: not provided Observation 1 Collection method: not provided Allele origin: unknown Affected status: not provided

Likely benign (Jun 19, 2024) N Not contributing to aggregate classification	no assertion criteria provided	LTBP2-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005349762.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

This variant has been reported in the heterozygous state in one individual with primary open angle glaucoma and one with pseudoexfoliation syndrome (Jelodari-Mamaghani 2013 PMID:23401661). However, this variant is present in 0.8% (245/30610) of South Asian alleles in the Genome Aggregation Database, and in 1 homozygote in each of v2.1.1 and v3.1.2 (https://gnomad.broadinstitute.org/variant/14-75018994-G-A?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.

Comment:

NM_000428.2:c.1295C>T in the LTBP2 gene has an allele frequency of 0.008 in South Asian subpopulation in the gnomAD database. The c.1295C>T (p.Pro432Leu) variant has been observed in a patient affected with pseudoexfoliation glaucoma (PEXG) syndrome (PMID: 23401661). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Contribution of the latent transforming growth factor-β binding protein 2 gene to etiology of primary open angle glaucoma and pseudoexfoliation syndrome.	Jelodari-Mamaghani S	Molecular vision	2013	PMID: 23401661

Text-mined citations for rs137854861 ...

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 Jun 20, 2026