15-51341743-T-C

Position:

• chr15-51341743-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_181789.4(GLDN):​c.59T>C​(p.Leu20Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GLDN NM_181789.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.83

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_181789.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 15-51341743-T-C is Pathogenic according to our data. Variant chr15-51341743-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 813924.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-51341743-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDN	NM_181789.4	c.59T>C	p.Leu20Pro	missense_variant	1/10	ENST00000335449.11
GLDN	XM_017022121.2	c.59T>C	p.Leu20Pro	missense_variant	1/9
GLDN	XM_017022125.1	c.59T>C	p.Leu20Pro	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDN	ENST00000335449.11	c.59T>C	p.Leu20Pro	missense_variant	1/10	2	NM_181789.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1311044 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 645912

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal congenital contracture syndrome 11 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Dec 03, 2018

The heterozygous p.Leu20Pro variant in GLDN was identified by our study in the compound heterozygous state, with a VUS, in three siblings with lethal congenital contracture syndrome. This variant segregated with disease in all three siblings, and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies conducted by our collaborators provide some evidence that the p.Leu20Pro variant may impact protein function by preventing localization to the cell membrane in cell-based assays, similarly to other variants identified in individuals with Lethal Arthrogyposis (PMID: 27616481). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PP1 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.012	D
Polyphen		0.053	B
Vest4		0.73
MutPred		0.65		Gain of loop (P = 0.002);
MVP		0.93
MPC		2.4
ClinPred		0.79	D
GERP RS		3.4
Varity_R		0.71
gMVP		0.82

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

Other links and lift over

dbSNP: rs1595795307; hg19: chr15-51633940;