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

gnomAD frequency: 0.00003  dbSNP: rs757820624

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2021-10-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004529370	SCV000915194	likely pathogenic	SLC26A4-related disorder	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001232144	SCV001404690	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 724 of the SLC26A4 protein (p.Asp724Gly). This variant is present in population databases (rs757820624, gnomAD 0.004%). This missense change 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 being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228396). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 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.
GeneDx	RCV001232144	SCV001874181	pathogenic	not provided	2022-10-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on iodide transport (Pera et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18285825, 27344577, 20668687, 19017801, 24224479, 14679580, 25491636, 19509082, 15811013, 15355436, 24860705, 31589614, 33199029)
Genome-Nilou Lab	RCV000984220	SCV002026976	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001232144	SCV003814612	likely pathogenic	not provided	2022-05-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474997	SCV004201826	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-02-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000984220	SCV001132294	likely pathogenic	Pendred syndrome	2018-10-24	no assertion criteria provided	clinical testing