chr5-69433088-C-T

Position:

chr5-69433088-C-T

Variant summary

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

The ENST00000325631.10(MARVELD2):c.1498C>T(p.Arg500Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,612,640 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

MARVELD2
ENST00000325631.10 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.97

Variant links:

Genes affected

MARVELD2 (HGNC:26401): (MARVEL domain containing 2) The protein encoded by this gene is a membrane protein found at the tight junctions between epithelial cells. The encoded protein helps establish epithelial barriers such as those in the organ of Corti, where these barriers are required for normal hearing. Defects in this gene are a cause of deafness autosomal recessive type 49 (DFNB49). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

MARVELD2 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 5-69433088-C-T is Pathogenic according to our data. Variant chr5-69433088-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-69433088-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARVELD2	NM_001038603.3 linkuse as main transcript	c.1498C>T	p.Arg500Ter	stop_gained	5/7	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10 linkuse as main transcript	c.1498C>T	p.Arg500Ter	stop_gained	5/7	1	NM_001038603.3	ENSP00000323264	P1	Q8N4S9-1

Frequencies

GnomAD3 genomes

AF:

0.0000860

AC:

AN:

151152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251192

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.000202

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000289

AC:

423

AN:

1461488

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000369

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000860

AC:

AN:

151152

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73636

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000967

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 49

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Deafness 49 (MIM#610153). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (26 heterozygotes, 0 homozygotes). (SP) 0701 - Many NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, PMID: 23767834, 33597575). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in individuals with hearling loss (ClinVar, PMID: 17186462, 31850270) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 30, 2018	The MARVELD2 c.1498C>T (p.Arg500Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg500Ter variant is reported in a homozygous state in eight individuals from one family with nonsyndromic hearing loss (Riazuddin et al. 2006). The p.Arg500Ter variant was shown to segregate with the disease and was absent from 443 normal hearing subjects matched for ethnicity. The p.Arg500Ter variant is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Arg500Ter variant disrupts the binding of the occludin domain to the scaffolding protein ZO-1 (Riazuddin et al. 2006). Nayak et al. (2013) generated knockin mice that were homozygous for the p.Arg500Ter variant and demonstrated ultrastructural changes in the tricellular junctions in all sensory and nonsensory epithelia of the inner ear organs and cochlear hair cell loss. Vax-Drago et al. (2015) demonstrated that, in a cell line derived from an individual who was homozygous for the p.Arg500Ter variant, total cellular mRNA levels were reduced compared to wild type, especially in the cytoplasmic fraction. Based on the evidence and the potential impact of stop-gained variants, the p.Arg500Ter variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2023

Published functional studies demonstrate that this variant results in disrupted MARVELD2 ZO-1 binding capacity, mislocalization of the protein from the tricellular junctions, and non-specific targeting of the mutant protein to basolateral domains of transfected cells (Nayak et al., 2013; Nayak et al., 2015); Nonsense variant in the C-terminus predicted to result in protein truncation, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 17186462, 25666562, 25652404, 25525159, 28705832, 29752989, 30406641, 31850270, 31589614, 26226137, 23979167) -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 19, 2014

The p.Arg500X variant in MARVELD2 has been previously reported in one individual with hearing loss and segregated with disease in 7 affected relatives from one family (Riazuddin 2006). It has also been identified in 0.018% (23/126596) of E uropean chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant creates a premature termination codon at position 500 and is predicted t o lead to a truncated or absent protein. Functional and animal studies support t he pathogenicity of the p.Arg500X variant (Riazuddin 2006, Nayak 2013). In summa ry, this variant meets criteria to be classified as pathogenic for autosomal rec essive sensorineural hearing loss. ACMG/AMP Criteria applied: PM3_Supporting, P P1_Strong, PVS1, PS3. -

Ear malformation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.86, 0.85, 0.66

GERP RS

4.8

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