Submissions for variant NM_194248.3(OTOF):c.1544T>C (p.Ile515Thr) (rs80356586)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000604852	SCV000710845	likely pathogenic	Rare genetic deafness	2017-02-14	criteria provided, single submitter	clinical testing	The p.Ile515Thr (NM_194248.2 c.1544T>C, ClinVar Variation ID#6143) variant in OT OF has been reported in 1 compound heterozygous individual with hearing loss who had a temperature-sensitive auditory neuropathy phenotype, in trans with a nons ense variant, and segregated with disease in an affected family member (Varga 20 06, Strenzke 2016, Avraham 2016). This variant has also been reported in 1 homoz ygous individual with hearing loss and in 3 affected homozygous family members, who all had a second missense OTOF variant of uncertain significance in cis (Mir ghomizadeh 2002). A knock-in mouse model homozygous for the p.Ile515Thr variant was shown to have hearing loss (Strenzke 2016). This variant has also been ident ified in 0.002% (1/65,772) of European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80356586). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p.Ile515 Thr variant is likely pathogenic for OTOF-related hearing loss in an autosomal r ecessive manner based upon biallelic observations in patients, low frequency in controls, and an animal model.
OMIM	RCV000006517	SCV000026700	pathogenic	Auditory neuropathy, autosomal recessive, 1	2006-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000021035	SCV000041689	association	Deafness, autosomal recessive 9	2015-07-30	no assertion criteria provided	literature only
OMIM	RCV000021035	SCV000222658	pathogenic	Deafness, autosomal recessive 9	2006-07-01	no assertion criteria provided	literature only

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