rs200334298

Positions:

• chr1-228158992-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000366714.3(GJC2):​c.1234C>T​(p.His412Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000956 in 1,603,620 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (3 hom.)
• Consequence: GJC2 ENST00000366714.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10 B:2
• Conservation: PhyloP100: 4.83

Genes affected

GJC2 (HGNC:17494): (gap junction protein gamma 2) This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.089141846).
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJC2	NM_020435.4	c.1234C>T	p.His412Tyr	missense_variant	2/2	ENST00000366714.3	NP_065168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3	c.1234C>T	p.His412Tyr	missense_variant	2/2	1	NM_020435.4	ENSP00000355675	P1

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000748 AC: 169 AN: 225966 Hom.: 0 AF XY: 0.000719 AC XY: 90 AN XY: 125230

Gnomad AFR exome AF: 0.0000805

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.000629

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000681

Gnomad FIN exome AF: 0.000428

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000715

GnomAD4 exome AF: 0.000959 AC: 1392 AN: 1451458 Hom.: 3 Cov.: 33 AF XY: 0.000938 AC XY: 677 AN XY: 721648

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.000655

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.000801

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000920

GnomAD4 genome AF: 0.000927 AC: 141 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.000700 AC XY: 52 AN XY: 74324

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000971

ExAC AF: 0.000797 AC: 89

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 23, 2023	The GJC2 c.1234C>T; p.His412Tyr variant (rs200334298), also known as H409Y, is reported in the literature in individuals affected with vascular and lymphatic malformations (Finegold 2012, Michelini 2016, Serio 2022). Additionally, this variant has been reported in an individual with Pelizaeus-Merzbacher-like disease, a form of hypomyelinating leukodystrophy (Zittel 2012). This variant is found in the non-Finnish European population with an allele frequency of 0.1402% (161/114,842 alleles) in the Genome Aggregation Database. Functional analyses of the variant protein show impaired function (Finegold 2012). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.5). While this variant is unlikely to be causative of autosomal dominant lymphatic malformations, due to limited and conflicting information, its clinical significance in recessive disease is uncertain at this time. References: Finegold DN et al. Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. Clin Cancer Res. 2012 Apr 15;18(8):2382-90. PMID: 22351697. Michelini S et al. Genetic Screening in a Large Cohort of Italian Patients Affected by Primary Lymphedema Using a Next Generation Sequencing (NGS) Approach. Lymphology. 2016 Jun;49(2):57-72. PMID: 29906362. Serio VB et al. Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy. J Clin Med. 2022 Jun 28;11(13):3740. PMID: 35807022. Zittel S et al. "Pelizaeus-Merzbacher-like disease" presenting as complicated hereditary spastic paraplegia. J Neurol. 2012 Nov;259(11):2498-500. PMID: 22833003. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2019	Identified in individual with segmental dystonia, spasticity, and hypomyelination who also harbored 2 additional GJC2 variants (Zittel et al., 2012); Published functional studies demonstrate impaired transfer of Lucifer yellow dye in cells transfected with H412Y (described as H409Y), supporting altered gap junction function (Finegold et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22351697, 29906362, 22833003) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 05, 2021	- -

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 412 of the GJC2 protein (p.His412Tyr). This variant is present in population databases (rs200334298, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lymphedema and/or Pelizaeus-Merzbacher-like disease (PMID: 22351697, 22833003, 29906362). This variant is also known as H409Y. ClinVar contains an entry for this variant (Variation ID: 445910). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJC2 protein function. Experimental studies have shown that this missense change affects GJC2 function (PMID: 22351697). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 19, 2023

Variant summary: GJC2 c.1234C>T (p.His412Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 225966 control chromosomes (genomAD). c.1234C>T has been reported in the literature in individuals affected with lymphedema or PelizaeusMerzbacher-like disease (Finegold_2012, Zittel_2012, Michelini_2016). These reports do not provide unequivocal conclusions about association of the variant with Hypomyelinating Leukodystrophy 2. At least one functional study reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Finegold_2012). Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. The following publications have been ascertained in the context of this evaluation (PMID: 22351697, 29906362, 35807022, 22833003). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.1234C>T (p.H412Y) alteration is located in exon 2 (coding exon 1) of the GJC2 gene. This alteration results from a C to T substitution at nucleotide position 1234, causing the histidine (H) at amino acid position 412 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2018

- -

Hypomyelinating leukodystrophy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Feb 11, 2021

This missense variant (c.1234C>T, p.His214Tyr) has been observed at very low frequency in population databases. It has been reported in the literature (PMID:22351697, PMID 22833003). Variant prediction programs provide no consensus as to the pathogenicity of the variant, and no functional studies have been published. -

Hypomyelinating leukodystrophy 2;C2750784:Hereditary spastic paraplegia 44;C4747646:Lymphatic malformation 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.089	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.50
Sift	Benign	0.037	D
Sift4G	Uncertain	0.058	T
Polyphen		0.10	B
Vest4		0.71
MVP		0.93
ClinPred		0.047	T
GERP RS		2.9
Varity_R		0.16
gMVP		0.12

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: rs200334298; hg19: chr1-228346693;