Submissions for variant NM_001384474.1(LOXHD1):c.3673A>G (p.Ser1225Gly)

gnomAD frequency: 0.00103  dbSNP: rs370149278

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150974	SCV000198651	uncertain significance	not specified	2013-06-07	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ser1225Gly vari ant in LOXHD1 has not been reported in individuals with hearing loss, but has be en identified in 0.6% (9/1384) of African American chromosomes by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is not high enough to rul e out a pathogenic role. Computational analyses (biochemical amino acid properti es, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, the clinical significance o f this variant cannot be determined with certainty; however, based upon presence in the general population in the absence of any data to support a role in heari ng loss, we would lean towards a more likely benign role.
Illumina Laboratory Services, Illumina	RCV000391936	SCV000408733	uncertain significance	Autosomal recessive nonsyndromic hearing loss 77	2018-01-12	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001452046	SCV001655693	likely benign	not provided	2025-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002516032	SCV003752954	uncertain significance	Inborn genetic diseases	2022-01-10	criteria provided, single submitter	clinical testing	The c.3673A>G (p.S1225G) alteration is located in exon 24 (coding exon 24) of the LOXHD1 gene. This alteration results from a A to G substitution at nucleotide position 3673, causing the serine (S) at amino acid position 1225 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003965124	SCV004779995	likely benign	LOXHD1-related disorder	2023-06-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).