Submissions for variant NM_000441.2(SLC26A4):c.1281TGC[1] (p.Ala429del)

dbSNP: rs111033306

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036434	SCV000060089	pathogenic	Rare genetic deafness	2018-10-04	criteria provided, single submitter	clinical testing	The p.Ala429del variant in SLC26A4 has been reported in at least 10 individuals with hearing loss, most of who were also reported to have temporal bone abnormal ities and/or Pendred syndrome (Coyle 1998, Prasad 2004, Dahl 2013, Rendtorff 201 3, Sloan-Heggen 2016, LMM data). At least 6 of these individuals were compound h eterozygous for additional pathogenic variants in SLC26A4 (Dahl 2013, Rentorff 2 013, Sloan-Heggen 2016, LMM data). This variant has also been identified in 0.01 % (14/126202) of European chromosomes by gnomAD (http://gnomad.broadinstitute.or g); however, its frequency is low enough to be consistent with a recessive carri er frequency. This variant is a deletion of 1 amino acid at position 429 and is not predicted to alter the protein reading frame. In summary, this variant meets our criteria to be classified as pathogenic for hearing loss with EVA and/or Pe ndred syndrome in an autosomal recessive manner based on its occurrence with pat hogenic SLC26A4 variants in several compound heterozygous affected individuals. ACMG/AMP Criteria applied: PM3_Very Strong, PM2_Supporting, PM4_Supporting.
Counsyl	RCV000169051	SCV000220211	likely pathogenic	Pendred syndrome	2014-04-01	criteria provided, single submitter	literature only
Baylor Genetics	RCV000169051	SCV001163094	likely pathogenic	Pendred syndrome		criteria provided, single submitter	clinical testing
Invitae	RCV001209562	SCV001381002	pathogenic	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This variant, c.1284_1286del, results in the deletion of 1 amino acid(s) of the SLC26A4 protein (p.Ala429del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs775837019, gnomAD 0.01%). This variant has been observed in individual(s) with deafness and/or Pendred syndrome (PMID: 21366435, 23336812, 25394566, 26969326; Invitae). 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: 43501). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001209562	SCV001874248	likely pathogenic	not provided	2023-01-19	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14679580, 21704276, 26969326, 23555729, 9618167, 23336812, 20668687, 25394566, 21366435, 31589614, 33199029)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470729	SCV002768935	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews) (I) 0216 - In-frame insertion/deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative missense amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0600 - Variant is located in the annotated sulfate permease family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten unrelated individuals with SLC26A4-related conditions (ClinVar, PMIDs:14679580, 21704276, 23336812, 23555729, 2696326, 9618167). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002482977	SCV002801607	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2022-02-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169051	SCV003800766	pathogenic	Pendred syndrome	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1284_1286delTGC (p.Ala429del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 6e-05 in 250844 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (6e-05 vs 0.0035), allowing no conclusion about variant significance. c.1284_1286delTGC has been reported in the literature in multiple compound heterozygous individuals affected with Pendred Syndrome (e.g., Mercer_2011, Sloan-Heggen_2016, Rendtorff_2013, Prasad_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) have cited the variant, with three laboratories classify the variant as pathogenic and three classifying the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV002470729	SCV004201918	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-06-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169051	SCV001459925	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing