MARVELD2 p.Arg500*

Variant names:

• chr5-69433088-C-T
• rs118203957
• NM_001038603.3:c.1498C>T
• MARVELD2 p.Arg500*

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS1_Supporting

The NM_001038603.3(MARVELD2):​c.1498C>T​(p.Arg500*) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000206314: Functional and animal studies support the pathogenicity of the p.Arg500X variant (Riazuddin 2006, Nayak 2013)." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: MARVELD2 NM_001038603.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.97
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 49

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000206314: Functional and animal studies support the pathogenicity of the p.Arg500X variant (Riazuddin 2006, Nayak 2013).; SCV000329411: 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 (PMID: 23979167, 25666562); SCV000916107: 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).
• PP5: Variant 5-69433088-C-T is Pathogenic according to our data. Variant chr5-69433088-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000289 (423/1461488) while in subpopulation NFE AF = 0.000369 (410/1111950). AF 95% confidence interval is 0.000339. There are 0 homozygotes in GnomAdExome4. There are 189 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001038603.3. 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
	MARVELD2	NM_001038603.3	MANE Select	c.1498C>T	p.Arg500*	stop_gained	Exon 5 of 7	NP_001033692.2	Q8N4S9-1
	MARVELD2	NM_001244734.2		c.1462C>T	p.Arg488*	stop_gained	Exon 4 of 6	NP_001231663.1	Q8N4S9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	ENST00000325631.10	TSL:1 MANE Select	c.1498C>T	p.Arg500*	stop_gained	Exon 5 of 7	ENSP00000323264.5	Q8N4S9-1
	MARVELD2	ENST00000454295.6	TSL:1	c.1462C>T	p.Arg488*	stop_gained	Exon 4 of 6	ENSP00000396244.2	Q8N4S9-3
	MARVELD2	ENST00000413223.3	TSL:1	n.1150C>T		non_coding_transcript_exon	Exon 5 of 8	ENSP00000398922.2	A1BQX2

Frequencies

GnomAD3 genomes AF: 0.0000860 AC: 13 AN: 151152 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000995 AC: 25 AN: 251192 AF XY: 0.000110

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 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.: 0 Cov.: 34 AF XY: 0.000260 AC XY: 189 AN XY: 727060

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000369 AC: 410 AN: 1111950

Other (OTH) AF: 0.000166 AC: 10 AN: 60390

GnomAD4 genome AF: 0.0000860 AC: 13 AN: 151152 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73636

African (AFR) AF: 0.00 AC: 0 AN: 41072

American (AMR) AF: 0.0000660 AC: 1 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Autosomal recessive nonsyndromic hearing loss 49 (5)
2	-	-	not provided (2)
1	-	-	Ear malformation (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		3.0
Mutation Taster		=0/200	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs118203957;

hg19: chr5-68728915;