ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.2171A>G (p.Asp724Gly) (rs757820624)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824772 SCV000271452 likely pathogenic Rare genetic deafness 2019-10-30 criteria provided, single submitter clinical testing The p.Asp724Gly variant in SLC26A4 has been previously reported in three individuals with hearing loss and EVA or Pendred syndrome who were compound heterozygous with a pathogenic variant (Prasad 2004, Arellano 2005, Ladsous 2014). A different missense variant at the same position (p.Asp724Asn) has also been reported in one individual with Pendred syndrome who was compound heterozygous for a second pathogenic variant (Blons 2004). In addition, in vitro functional studies suggest the variant impairs the normal function of the protein (Pera 2008), and computational and conservation analysis support a deleterious effect. The variant has also been identified in 0.008% (2/24966) of African chromosomes by gnomAD; however this frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp724Gly variant is likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PS3_Supporting, PP4, PP3.
Fulgent Genetics,Fulgent Genetics RCV000218320 SCV000893732 likely pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778814 SCV000915194 likely pathogenic SLC26A4-Related Disorders 2018-12-03 criteria provided, single submitter clinical testing The SLC26A4 c.2171A>G (p.Asp724Gly) missense variant has been reported in at least three studies and is found in a total of four probands, including three probands in a compound heterozygous state and one proband in a heterozygous state (Prasad et al. 2004; Pera et al. 2008; Ladsous et al. 2014). Of the three compound heterozygous probands; two probands were clinically diagnosed with Pendred syndrome and one proband was noted to have non-syndromic enlarged vestibular aqueduct. The heterozygous proband was described to have non-syndromic hearing loss, although an alternate etiology was suspected to be causative, this phenotype and thus this proband was considered a coincidental carrier of the p.Asp724Gly variant (Pera et al. 2008). The p.Asp724Gly variant was reported in two of 648 controls alleles and is reported at a frequency of 0.000032 in the European (non-Finnish) population of the Genome Aggregation Database. The Asp724 residue is highly conserved. The p.Asp724Gly variant protein was expressed in HEK-293 phoenix cells and had no detectable iodide transport when analyzed with fluorometry, indicating complete inactivation in comparison to wildtype (Pera et al. 2008). Based on the evidence, the p.Asp724Gly variant is classified as likely pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001232144 SCV001404690 pathogenic not provided 2020-06-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 724 of the SLC26A4 protein (p.Asp724Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs757820624, ExAC 0.02%). This variant has been observed in individual(s) with Pendred syndrome or nonsyndromic enlarged vestibular aqueduct (PMID: 14679580, 15811013, 24224479). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228396). This variant has been reported to affect SLC26A4 protein function (PMID: 19017801). This variant disrupts the p.Asp724 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 15355436, 27344577), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000984220 SCV001132294 likely pathogenic Pendred syndrome 2018-10-24 no assertion criteria provided clinical testing

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