rs121918355

Variant names:

• chr14-74555629-G-A
• rs121918355
• NM_000428.3:c.895C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-74555629-G-A
• chr14-74555629-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000428.3(LTBP2):​c.895C>T​(p.Arg299*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,444,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: LTBP2 NM_000428.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.92
• Publications: 24 publications found

Genes affected

LTBP2 (HGNC:6715): (latent transforming growth factor beta binding protein 2) The protein encoded by this gene belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is the largest member of the LTBP family possessing unique regions and with most similarity to the fibrillins. It has thus been suggested that it may have multiple functions: as a member of the TGF-beta latent complex, as a structural component of microfibrils, and a role in cell adhesion. [provided by RefSeq, Jul 2008]

LTBP2 Gene-Disease associations (from GenCC):

• glaucoma 3, primary congenital, D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Weill-Marchesani syndrome 3

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glaucoma secondary to spherophakia/ectopia lentis and megalocornea

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258425 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-74555629-G-A is Pathogenic according to our data. Variant chr14-74555629-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000428.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP2	NM_000428.3	MANE Select	c.895C>T	p.Arg299*	stop_gained	Exon 4 of 36	NP_000419.1	Q14767

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP2	ENST00000261978.9	TSL:1 MANE Select	c.895C>T	p.Arg299*	stop_gained	Exon 4 of 36	ENSP00000261978.4	Q14767
	LTBP2	ENST00000945197.1		c.895C>T	p.Arg299*	stop_gained	Exon 4 of 35	ENSP00000615256.1
	LTBP2	ENST00000556690.5	TSL:5	c.895C>T	p.Arg299*	stop_gained	Exon 4 of 35	ENSP00000451477.1	G3V3X5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000208 AC: 5 AN: 240674 AF XY: 0.0000231

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1444814 Hom.: 0 Cov.: 32 AF XY: 0.0000112 AC XY: 8 AN XY: 716232

African (AFR) AF: 0.00 AC: 0 AN: 33180

American (AMR) AF: 0.00 AC: 0 AN: 43744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25448

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39278

South Asian (SAS) AF: 0.00 AC: 0 AN: 84510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1100468

Other (OTH) AF: 0.00 AC: 0 AN: 59584

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000154 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Glaucoma 3, primary congenital, D (1)
1	-	-	Microspherophakia (1)
1	-	-	Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		2.9
Vest4		0.74
GERP RS		4.8
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918355; hg19: chr14-75022332; COSMIC: COSV56204588;