rs373848470
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001384474.1(LOXHD1):c.6055G>A(p.Glu2019Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000293 in 1,549,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E2019E) has been classified as Likely benign.
Frequency
Consequence
NM_001384474.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LOXHD1 | NM_001384474.1 | c.6055G>A | p.Glu2019Lys | missense_variant | 39/41 | ENST00000642948.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LOXHD1 | ENST00000642948.1 | c.6055G>A | p.Glu2019Lys | missense_variant | 39/41 | NM_001384474.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000227 AC: 34AN: 150080Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000133 AC: 21AN: 158384Hom.: 0 AF XY: 0.000108 AC XY: 9AN XY: 83568
GnomAD4 exome AF: 0.000300 AC: 420AN: 1399190Hom.: 0 Cov.: 35 AF XY: 0.000284 AC XY: 196AN XY: 690060
GnomAD4 genome ? AF: 0.000227 AC: 34AN: 150080Hom.: 0 Cov.: 30 AF XY: 0.000192 AC XY: 14AN XY: 73016
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 77 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 18, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 14, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2021 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1957 of the LOXHD1 protein (p.Glu1957Lys). This variant is present in population databases (rs373848470, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LOXHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 179310). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2022 | Reported previously in an individual with autosomal recessive hearing loss, who was heterozygous for E1957K and two other variants (L577R and R1982X); however, familial segregation information was not included to determine phase of these variants (Sloan-Heggen et al., 2016); 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: 31547530, 31709873, 26969326) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | LOXHD1: PM2 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 24, 2019 | The p.Glu1957Lys variant in LOXHD1 has been previously reported in 2 individual with hearing loss, one of whom also harbored two additional LOXHD1 variants (p.Leu577Arg and p.Arg933X) and the other also carried the p.Leu577Arg, though cis/trans phasing was not determined for either individual (Sloan-Heggen 2016; LMM unpublished data). This variant has been identified in 0.03% (23/77048) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3_Supporting, PP3. - |
LOXHD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2023 | The LOXHD1 c.5869G>A variant is predicted to result in the amino acid substitution p.Glu1957Lys. This variant (also known as c.2722G>A, p.Glu908Lys in NM_001145472) has been reported in at least one individual with a hearing loss phenotype. However, two other variants in LOXHD1 were also detected in this individual (Patient 161, Table S3, Sloan-Heggen et al. 2016. PubMed ID: 26969326). This variant is reported in 0.030% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at