18-46560448-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001384474.1(LOXHD1):c.2696G>C(p.Arg899Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,543,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R899Q) has been classified 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.2696G>C | p.Arg899Pro | missense_variant | 19/41 | ENST00000642948.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.2696G>C | p.Arg899Pro | missense_variant | 19/41 | NM_001384474.1 | P1 | ||
LOXHD1 | ENST00000536736.5 | c.2696G>C | p.Arg899Pro | missense_variant | 19/40 | 5 | |||
LOXHD1 | ENST00000441551.6 | c.2598+2617G>C | intron_variant | 5 | |||||
LOXHD1 | ENST00000335730.6 | n.2009G>C | non_coding_transcript_exon_variant | 12/27 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000256 AC: 39AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000179 AC: 27AN: 150590Hom.: 0 AF XY: 0.000225 AC XY: 18AN XY: 80000
GnomAD4 exome AF: 0.000488 AC: 679AN: 1391348Hom.: 0 Cov.: 37 AF XY: 0.000460 AC XY: 316AN XY: 686620
GnomAD4 genome AF: 0.000256 AC: 39AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74348
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2023 | Observed multiple times with another LOXHD1 variant in unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Sloan-Heggen et al., 2016; Wesdorp et al., 2018; Shen et al., 2019); 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: 32149082, 29676012, 26969326, 30760222, 31547530, 31709873, 32860223, Morlet2021[Case Report], 33892339, 35875410) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 899 of the LOXHD1 protein (p.Arg899Pro). This variant is present in population databases (rs745683775, gnomAD 0.04%). This missense change has been observed in individual(s) with deafness (PMID: 26969326, 29676012, 32860223; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228819). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 01, 2017 | - - |
Autosomal recessive nonsyndromic hearing loss 77 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 07, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Nonsyndromic genetic hearing loss Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 03, 2022 | Variant summary: LOXHD1 c.2696G>C (p.Arg899Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 150590 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.2696G>C has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 77 ( examples: Sloan-Heggen_2016, Wesdorp_2018, Brozkova_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014: VUS (n=4) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 15, 2016 | The p.Arg899Pro variant in LOXHD1 has not been previously reported in individual s with hearing loss. Data from large population studies are insufficient to asse ss the frequency of this variant. Computational prediction tools and conservatio n analyses do not provide strong support for or against an impact to the protein . In summary, the clinical significance of the p.Arg899Pro variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at