rs747013505

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000308370.11(LTBP4):c.365del(p.Leu122ArgfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,261,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

LTBP4
ENST00000308370.11 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.46

Variant links:

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-40600090-CT-C is Pathogenic according to our data. Variant chr19-40600090-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP4	NM_001042544.1 linkuse as main transcript	c.365del	p.Leu122ArgfsTer15	frameshift_variant	4/33
LTBP4	NM_003573.2 linkuse as main transcript	c.254del	p.Leu85ArgfsTer15	frameshift_variant	4/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Appris	UniProt
LTBP4	ENST00000308370.11 linkuse as main transcript	c.365del	p.Leu122ArgfsTer15	frameshift_variant	4/33	1	A2	Q8N2S1-1
LTBP4	ENST00000204005.13 linkuse as main transcript	c.254del	p.Leu85ArgfsTer15	frameshift_variant	4/33	1	A2
LTBP4	ENST00000593738.1 linkuse as main transcript	n.108del		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000919

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000114

AC:

AN:

26376

Hom.:

AF XY:

0.0000823

AC XY:

AN XY:

12148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000279

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

157

AN:

1108952

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

525768

show subpopulations

Gnomad4 AFR exome

AF:

0.0000432

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000164

Gnomad4 OTH exome

AF:

0.0000902

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25714468, 28654958, 30487145, 29565423, 29030401, 31256874, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Leu85Argfs*15) in the LTBP4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LTBP4 are known to be pathogenic (PMID: 19836010, 22829427). This variant is present in population databases (rs747013505, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LTBP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 189236). For these reasons, this variant has been classified as Pathogenic. -

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 17, 2014

The Leu85ArgfsX15 variant in LTBP4 has not been previously reported in individuals with autosomal recessive cutis laxa type I, but has been identified in 1/5840 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 85 and lead to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of LTBP4 function has previously been desribed in homozygous and compound heterozygous individuals with autosomal recessive cutis laxa type IC (Urban 2009, Callewaert 2013). In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive cutis laxa type IC (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over