15-51341766-G-C

Position:

chr15-51341766-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_181789.4(GLDN):c.82G>C(p.Ala28Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000134 in 1,490,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GLDN
NM_181789.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.80

Variant links:

Genes affected

GLDN (HGNC:29514): (gliomedin) This gene encodes a protein that contains olfactomedin-like and collagen-like domains. The encoded protein, which exists in both transmembrane and secreted forms, promotes formation of the nodes of Ranvier in the peripheral nervous system. Mutations in this gene cause a form of lethal congenital contracture syndrome in human patients. Autoantibodies to the encoded protein have been identified in sera form patients with multifocal motor neuropathy. [provided by RefSeq, May 2017]

GLDN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-51341766-G-C is Pathogenic according to our data. Variant chr15-51341766-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1175345.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDN	NM_181789.4 linkuse as main transcript	c.82G>C	p.Ala28Pro	missense_variant	1/10	ENST00000335449.11	NP_861454.2	Q6ZMI3-1
GLDN	XM_017022121.2 linkuse as main transcript	c.82G>C	p.Ala28Pro	missense_variant	1/9		XP_016877610.1
GLDN	XM_017022125.1 linkuse as main transcript	c.82G>C	p.Ala28Pro	missense_variant	1/10		XP_016877614.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDN	ENST00000335449.11 linkuse as main transcript	c.82G>C	p.Ala28Pro	missense_variant	1/10	2	NM_181789.4	ENSP00000335196.6		Q6ZMI3-1
GLDN	ENST00000560215.5 linkuse as main transcript	c.-33G>C		upstream_gene_variant		4		ENSP00000484633.1		A0A087X220

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000113

AC:

AN:

88468

Hom.:

AF XY:

0.00

AC XY:

AN XY:

50282

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:

0.0000292

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000134

AC:

AN:

1338690

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

660314

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000141

Gnomad4 OTH exome

AF:

0.0000539

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lethal congenital contracture syndrome 11

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 17, 2023	Variant summary: GLDN c.82G>C (p.Ala28Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 88468 control chromosomes. c.82G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Lethal Congenital Contracture Syndrome 11, including a homozygous affected individual with overlapping features identified at our laboratory (example, Eurich_2022, Laquerriere_2022, Potrony_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35740734, 33820833, 35806855). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Mar 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.8

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.83

REVEL

Uncertain

0.49

Sift

Benign

0.10

Sift4G

Benign

0.18

Polyphen

0.98

Vest4

0.50

MutPred

0.63

Loss of helix (P = 0.0237);

MVP

0.88

MPC

2.1

ClinPred

0.61

GERP RS

4.5

Varity_R

0.54

gMVP

0.84

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