rs111033241

Positions:

• chr7-107663422-GGCCAC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.294_298delCACGC​(p.Thr99fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.72

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107663422-GGCCAC-G is Pathogenic according to our data. Variant chr7-107663422-GGCCAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.294_298delCACGC	p.Thr99fs	frameshift_variant	3/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.294_298delCACGC	p.Thr99fs	frameshift_variant	3/21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000440056.1	c.294_298delCACGC	p.Thr99fs	frameshift_variant	3/4	4		ENSP00000394760.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 43551). This variant has not been reported in the literature in individuals affected with SLC26A4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr99Alafs*81) in the SLC26A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 27, 2019	- -

Pendred syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Nov 04, 2016

- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 29, 2023

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 08, 2015

The 294_298delCACGC variant is predicted to cause a frameshift, which alters th e protein?s amino acid sequence beginning at position 99 and leads to a prematur e termination codon 81 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. It was also identified in a patient o f Asian descent with hearing loss and bilateral temporal bone abnormalities and a second likely pathogenic variant c.706C>G (p.Leu236Val). -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033241; hg19: chr7-107303867;