Submissions for variant NM_001384474.1(LOXHD1):c.4714C>T (p.Arg1572Ter)

dbSNP: rs75949023

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211793	SCV000221196	pathogenic	Rare genetic deafness	2014-07-15	criteria provided, single submitter	clinical testing	The p.Arg1572X variant in LOXHD1 has been reported in 2 homozygous Ashkenazi Jew ish individuals with nonsyndromic hearing loss, and it was found to segregate wi th disease in 7 homozygous affected family members (Edvardson 2011). This varia nt has been identified in 6/8670 European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs75949023). Although th is variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 1572 which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic based upon segregation studies and the predicted imp act to the protein.
GeneDx	RCV000627214	SCV000748201	pathogenic	not provided	2024-04-05	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25792669, 25525159, 22341973, 26973026, 30096381, 29676012, 31547530, 25333069, 35875410, 31980526, 37240244, 30760222, 32149082, 35711932, 21465660)
Fulgent Genetics, Fulgent Genetics	RCV000023981	SCV000893496	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2021-11-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000023981	SCV000914816	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2018-10-22	criteria provided, single submitter	clinical testing	The LOXHD1 c.4714C>T (p.Arg1572Ter) variant is a stop-gained variant that is predicted to cause a premature truncation of the protein. The p.Arg1572Ter variant has been reported in two studies in which it was found in a homozygous state in a total of nine probands from two unrelated, non-consanguineous Ashkenazi Jewish families and in a heterozygous state in an additional Ashkenazi Jewish proband in whom a second variant could not be identified (Edvardson et al. 2011; Tsai et al. 2013). In one of the families, the parents and three of the normal hearing siblings were found to be heterozygous for the variant, two unaffected siblings did not carry the variant, and five affected siblings were homozygous for the variant, suggesting that the variant segregated with disease in this family (Edvardson et al. 2011). In the second family, the four affected individuals were homozygous for the p.Arg1572Ter variant (Edvardson et al. 2011). The variant was reported in a heterozygous state in four out of 719 Ashkenazi Jewish controls and in one out of 44 healthy Ashkenazi Jewish centenarians (Edvardson et al. 2011; Freudenberg-Hua et al. 2014) and is reported at a frequency of 0.002922 in the Ashkenzi Jewish population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the available evidence, the p.Arg1572Ter variant is classified as likely pathogenic for autosomal recessive non-syndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627214	SCV000954684	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1572*) in the LOXHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LOXHD1 are known to be pathogenic (PMID: 19732867, 21465660, 25792669). This variant is present in population databases (rs75949023, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hearing loss (PMID: 21465660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30990). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000023981	SCV000045272	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2011-05-01	no assertion criteria provided	literature only
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000023981	SCV001164282	pathogenic	Autosomal recessive nonsyndromic hearing loss 77	2018-05-07	no assertion criteria provided	research	Recessive, congenital, severe-profound NSHL
PreventionGenetics, part of Exact Sciences	RCV004751222	SCV005348314	likely pathogenic	LOXHD1-related disorder	2024-09-01	no assertion criteria provided	clinical testing	The LOXHD1 c.4714C>T variant is predicted to result in premature protein termination (p.Arg1572*). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive non-syndromic hearing loss and has been noted to segregate with the disorder in families (Edvardson et al. 2011. PubMed ID: 21465660; Wang et al. 2022. PubMed ID: 35711932). Nonsense variants in LOXHD1 are expected to be pathogenic. This variant is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent and 0.0066% of alleles in individuals of non-Finnish European descent in gnomAD; in at least one study, this variant was suggested to be a founder variant in the Ashkenazi Jewish population (Edvardson et al. 2011. PubMed ID: 21465660). This variant is interpreted as likely pathogenic.