Submissions for variant NM_000441.2(SLC26A4):c.2145G>T (p.Lys715Asn)

dbSNP: rs397516427

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000675123	SCV001245156	likely pathogenic	Pendred syndrome	2023-08-22	reviewed by expert panel	curation	The c.2145G>T variant in SLC26A4 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 715 (p.Lys715Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06777% (95% CI of 29/30610) in the South Asian population (PM2_supporting, BS1, and BA1 not met). This variant has been observed in 3 probands with hearing loss in trans with another pathogenic or likely pathogenic variant (PM3_Strong; PMID: 26969326, PMID: 32417962, LMM unpublished data SCV000060131.6). At least one proband with this variant presented with clinical features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4; LMM unpublished data SCV000060131.6).This variant has been observed in several other cases where a second variant in SLC26A4 was not found (PMID: 19509082, 19287372, 26188157, 32417962). Functional studies including fluorescence assays and chloride exchange experiments have demonstrated that this variant impacts protein function (PS3_Supporting; PMID: 19509082). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 08/22/23: PM3_Strong, PS3_Supporting, PP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036476	SCV000060131	likely pathogenic	Rare genetic deafness	2012-03-22	criteria provided, single submitter	clinical testing	The Lys715Asn variant in SLC26A4 has been reported in a heterozygous state in th ree probands with hearing loss and was absent from 100 control samples (Dia 2009 , Anwar 2009). In addition, functional studies showed reduced Cl- anion exchange activity compared to the wild type (Dia 2009). Furthermore, the presence of thi s variant in combination with a pathogenic variant and in an individual with cli nical features of hearing loss and EVA, increases the likelihood that the Lys715 Asn variant is pathogenic. In summary, this variant is likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000585409	SCV000693248	likely pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000675123	SCV000800691	uncertain significance	Pendred syndrome	2018-04-10	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV000675123	SCV001571754	likely pathogenic	Pendred syndrome	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PM2_Supporting, BP4_Supporting
3billion	RCV002051802	SCV002318813	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC26A4 related disorder (PMID:19287372). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 26969326). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 19509082). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.831>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0001154). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002051802	SCV002767722	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from lysine to asparagine (exon 19). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (29 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (STAS domain; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with recessive deafness (ClinVar, Deafnessvariationdatabase, PMID: 19287372, PMID: 26969326, PMID: 25372295). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected Xenopus oocytes demonstrated impaired chloride efflux activity and protein transport (PMID: 19509082) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
GeneDx	RCV000585409	SCV004031992	uncertain significance	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Reported with a second variant (phase unknown) in unrelated patients with bilateral hearing loss referred for genetic testing at GeneDx and in published literature (Sloan-Heggen et al., 2016); Published functional studies suggest this variant demonstrates reduced anion exchange properties (Dai et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; Classified as uncertain significance by the ClinGen Hearing Loss Variant Curation Expert Panel (VCV000043541.24; Oza et al., 2018); This variant is associated with the following publications: (PMID: 28941661, 19509082, 26188157, 32417962, 18813951, 33614372, 25372295, 35186384, 26186295, 19287372, 25999548, 35249537, 26969326)
Baylor Genetics	RCV002051802	SCV004201855	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737175	SCV005342594	likely pathogenic	SLC26A4-related disorder	2024-08-02	no assertion criteria provided	clinical testing	The SLC26A4 c.2145G>T variant is predicted to result in the amino acid substitution p.Lys715Asn. This variant was reported in the compound heterozygous state in an individual with hearing loss as well as in a second individual who also had an enlarged vestibular aqueduct (Table S3, Sloan-Heggen et al. 2015. PubMed ID: 26445815; Chandru et al. 2020. PubMed ID: 32417962). In vitro experiments demonstrated this variant impacts protein function (Dai et al. 2009. PubMed ID: 19509082). This variant is reported in 0.095% of alleles in individuals of South Asian descent in gnomAD and is classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/43541/). This variant is interpreted as likely pathogenic.