rs727503146
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001384474.1(LOXHD1):βc.2303delβ(p.Gly768AlafsTer165) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000773 in 1,551,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.0000079 ( 0 hom. )
Consequence
LOXHD1
NM_001384474.1 frameshift
NM_001384474.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.30
Genes affected
LOXHD1 (HGNC:26521): (lipoxygenase homology PLAT domains 1) This gene encodes a highly conserved protein consisting entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains, thought to be involved in targeting proteins to the plasma membrane. Studies in mice show that this gene is expressed in the mechanosensory hair cells in the inner ear, and mutations in this gene lead to auditory defects, indicating that this gene is essential for normal hair cell function. Screening of human families segregating deafness identified a mutation in this gene which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]
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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
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Very rare variant in population databases, with high coverage;
PP5
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Variant 18-46566390-GC-G is Pathogenic according to our data. Variant chr18-46566390-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 163919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-46566390-GC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.2303del | p.Gly768AlafsTer165 | frameshift_variant | 17/41 | ENST00000642948.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.2303del | p.Gly768AlafsTer165 | frameshift_variant | 17/41 | NM_001384474.1 | P1 | ||
LOXHD1 | ENST00000536736.5 | c.2303del | p.Gly768AlafsTer165 | frameshift_variant | 17/40 | 5 | |||
LOXHD1 | ENST00000441551.6 | c.2303del | p.Gly768AlafsTer113 | frameshift_variant | 17/39 | 5 | |||
LOXHD1 | ENST00000335730.6 | n.1616del | non_coding_transcript_exon_variant | 10/27 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000786 AC: 11AN: 1399182Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5AN XY: 690086
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 163919). This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly768Alafs*165) in the LOXHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LOXHD1 are known to be pathogenic (PMID: 19732867, 21465660, 25792669). - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 15, 2014 | The Gly768fs variant in LOXHD1 has not been previously identified in individuals with hearing loss and was absent from large population studies. This frameshift variant is predicted to alter the protein's amino acid sequence beginning at po sition 768 and lead to a premature termination codon 165 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Los s of function variants in the LOXHD1 gene have been previously reported to segre gate in affected individuals from several families with autosomal recessive nons yndromic hearing loss (Grillet 2009, Edvardson 2011). In summary, this variant m eets our criteria for pathogenicity (http://pcpgm.partners.org/LMM). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at