NM_001384474.1:c.1759C>T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001384474.1(LOXHD1):c.1759C>T(p.Arg587Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000715 in 1,551,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001384474.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.1759C>T | p.Arg587Trp | missense_variant | Exon 13 of 41 | ENST00000642948.1 | NP_001371403.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.1759C>T | p.Arg587Trp | missense_variant | Exon 13 of 41 | NM_001384474.1 | ENSP00000496347.1 | |||
LOXHD1 | ENST00000536736.5 | c.1759C>T | p.Arg587Trp | missense_variant | Exon 13 of 40 | 5 | ENSP00000444586.1 | |||
LOXHD1 | ENST00000441551.6 | c.1759C>T | p.Arg587Trp | missense_variant | Exon 13 of 39 | 5 | ENSP00000387621.2 | |||
LOXHD1 | ENST00000335730.6 | n.1072C>T | non_coding_transcript_exon_variant | Exon 6 of 27 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152170Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000883 AC: 14AN: 158588Hom.: 0 AF XY: 0.000120 AC XY: 10AN XY: 83514
GnomAD4 exome AF: 0.0000650 AC: 91AN: 1399452Hom.: 0 Cov.: 31 AF XY: 0.0000695 AC XY: 48AN XY: 690230
GnomAD4 genome AF: 0.000131 AC: 20AN: 152288Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74468
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 77 Uncertain:3
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A heterozygous missense variant, NM_144612.6(LOXHD1):c.1759C>T, has been identified in exon 13 of 40 of the LOXHD1 gene. The variant is predicted to result in a major amino acid change from an arginine to a tryptophan at position 587 of the protein, NP_653213.6(LOXHD1):p.(Arg587Trp). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster) and the variant is present in the gnomAD database at a frequency of 0.009322% (17 heterozygotes, 0 homozygotes). The variant has been previously described as a VUS in individuals with autosomal dominant late-onset Fuchs corneal dystrophy (ClinVar, Riazuddin et al., 2012), however it has not been reported in individuals with hearing loss. Also, missense variants in this gene are not a well established mutational mechanism. Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS). -
not provided Uncertain:3
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Reported along with a second variant in the LOXHD1 gene in a patient with sensorineural hearing loss in the published literature; however, segregation information was not provided (PMID: 31827275); Reported as a heterozygous variant in a patient with sensorineural hearing impairment in the published literature; however, a second variant in LOXHD1 gene was not reported (PMID: 25251670); Identified in a patient with late-onset Fuchs corneal dystrophy in published literature (PMID: 22341973); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25251670, 31827275, 22341973) -
not specified Uncertain:2
The p.Arg587Trp variant in LOXHD1 has not been previously reported in individual s with hearing loss, but has been identified in 1/198 Asian chromosomes by the 1 000 Genomes Project (dbSNP rs540100675). Computational prediction tools and cons ervation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg587Trp variant is unc ertain. -
Variant summary: LOXHD1 c.1759C>T (p.Arg587Trp) results in a non-conservative amino acid change located in the PLAT/LH2 domain (IPR001024) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 158588 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 (8.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.1759C>T has been reported in the literature in individuals affected with Congenital hearing impairment or Fuchs corneal dystrophy (e.g. Riazuddin_2012, Chai_2014, Downie_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed this variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at