Submissions for variant NM_001384474.1(LOXHD1):c.2T>A (p.Met1Lys)

gnomAD frequency: 0.02382  dbSNP: rs36024592

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041204	SCV000064895	benign	not specified	2012-12-20	criteria provided, single submitter	clinical testing	This variant has been identified in 4% (127/3182) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs36024592) . There is also a second Met amino acid t hat may serve as the start of translation.
GeneDx	RCV000041204	SCV000728660	benign	not specified	2017-08-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000665901	SCV000790102	benign	Autosomal recessive nonsyndromic hearing loss 77	2017-03-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000992282	SCV001144449	benign	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000665901	SCV001284606	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000992282	SCV001717027	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000665901	SCV001761398	likely benign	Autosomal recessive nonsyndromic hearing loss 77	2021-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041204	SCV002104083	benign	not specified	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: LOXHD1 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met2) is located in the encoded protein. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.032 in 154084 control chromosomes, predominantly at a frequency of 0.064 within the South Asian subpopulation in the gnomAD database, including 69 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 57 fold of the estimated maximal expected allele frequency for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000992282	SCV005215403	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000665901	SCV001454093	benign	Autosomal recessive nonsyndromic hearing loss 77	2020-09-16	no assertion criteria provided	clinical testing