ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.2T>C (p.Met1Thr) (rs111033302)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036489 SCV000060144 pathogenic Rare genetic deafness 2017-11-22 criteria provided, single submitter clinical testing The c.2T>C (p.Met1?) variant in SLC26A4 has been reported in at least 6 individu als with hearing loss and EVA, all of whom were compound heterozygous (Shears 20 04, Gardner 2006, Dai 2009, Choi 2009, Huang 2011, Ladsous 2014, LMM data). It h as been identified in 0.01% (14/87438) of European chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033302). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency for recessive hearing loss . This variant affects the translation initiation start codon (ATG) and is there fore predicted to disrupt translation. In vitro functional studies provide some evidence that the c.2T>C variant may impact protein function (Choi 2009). Additi onally, a different variant in the translation initiation start codon (c.3G>C) h as also been reported in an individual with hearing loss and EVA, supporting tha t changes to this codon are not tolerated. In summary, this variant meets crite ria to be classified as pathogenic for hearing loss in an autosomal recessive ma nner based on the predicted impact of the variant and multiple occurrences with pathogenic SLC26A4 variants in individuals with hearing loss. ACMG/AMP Criteria applied: PVS1; PM3_VeryStrong; PP4.
Invitae RCV000797012 SCV000936550 pathogenic not provided 2020-06-04 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. This variant is present in population databases (rs111033302, ExAC 0.01%). This variant has been observed to be de novo in an individual affected with severe hearing loss and an enlarged vestibular aqueduct (PMID: 27997596). It has also been observed in several other individuals with nonsyndromic sensorineural hearing loss and enlargement of vestibular aqueduct (PMID: 21961810, 23965030, 19509082, 25372295, 19204907). ClinVar contains an entry for this variant (Variation ID: 43553). Experimental studies have shown that this missense change disrupts SLC26A4 protein localization (PMID: 19204907). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001273161 SCV001481210 pathogenic Pendred syndrome 2019-10-11 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 14679580, 19204907, 21961810, 24224479]
Baylor Genetics RCV001329893 SCV001521449 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2020-01-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Neurogenetic Laboratory,Second Faculty of Medicine, Charles University RCV001329893 SCV001571601 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2021-03-30 criteria provided, single submitter clinical testing
Natera, Inc. RCV001273161 SCV001455790 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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