chr4-42963095-T-TTCCC

Variant names:

• chr4-42963095-T-TTCCC
• rs1553941938
• NM_001080476.3:c.594_597dupCCCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001080476.3(GRXCR1):​c.594_597dupCCCT​(p.Val200ProfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRXCR1 NM_001080476.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

GRXCR1 (HGNC:31673): (glutaredoxin and cysteine rich domain containing 1) This gene is one of 60 loci associated with autosomal-recessive nonsyndromic hearing impairment. This gene encodes a protein which contains GRX-like domains; these domains play a role in the S-glutathionylation of proteins and may be involved in actin organization in hair cells. [provided by RefSeq, Sep 2010]

GRXCR1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 4-42963095-T-TTCCC is Pathogenic according to our data. Variant chr4-42963095-T-TTCCC is described in ClinVar as Pathogenic. ClinVar VariationId is 504921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRXCR1	NM_001080476.3	c.594_597dupCCCT	p.Val200ProfsTer6	frameshift_variant	Exon 2 of 4	ENST00000399770.3	NP_001073945.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRXCR1	ENST00000399770.3	c.594_597dupCCCT	p.Val200ProfsTer6	frameshift_variant	Exon 2 of 4	1	NM_001080476.3	ENSP00000382670.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

May 01, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val200fs variant in GRXCR1 has been identified in the homozygous state by our laboratory in 1 individual with hearing loss and segregated in an affected s ibling (this family). This variant was absent from large population studies, tho ugh the ability of these studies to accurately detect indels may be limited. The p.Val200fs variant is predicted to cause a frameshift, which alters the protein ?s amino acid sequence beginning at position 200 and leads to a premature termin ation codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function (LoF) variants in the GRXCR1 have been reported in individuals with hearing loss, and a mouse model study sup ports LoF as a disease mechanism (Odeh 2010). In summary, the p.Val200fs variant meets our criteria to be classified as pathogenic for hearing loss in an autoso mal recessive manner based on the predicted impact of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553941938; hg19: chr4-42965112;