rs1336307815

Positions:

• chr15-43600074-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_153700.2(STRC):​c.5125A>G​(p.Thr1709Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000054 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 3.07

Genes affected

STRC (HGNC:16035): (stereocilin) This gene encodes a protein that is associated with the hair bundle of the sensory hair cells in the inner ear. The hair bundle is composed of stiff microvilli called stereocilia and is involved with mechanoreception of sound waves. This gene is part of a tandem duplication on chromosome 15; the second copy is a pseudogene. Mutations in this gene cause autosomal recessive non-syndromic deafness. [provided by RefSeq, Jul 2008]

CKMT1B (HGNC:1995): (creatine kinase, mitochondrial 1B) Mitochondrial creatine (MtCK) kinase is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. It belongs to the creatine kinase isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Many malignant cancers with poor prognosis have shown overexpression of ubiquitous mitochondrial creatine kinase; this may be related to high energy turnover and failure to eliminate cancer cells via apoptosis. Ubiquitous mitochondrial creatine kinase has 80% homology with the coding exons of sarcomeric mitochondrial creatine kinase. Two genes located near each other on chromosome 15 have been identified which encode identical mitochondrial creatine kinase proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 15-43600074-T-C is Pathogenic according to our data. Variant chr15-43600074-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43600074-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2	c.5125A>G	p.Thr1709Ala	missense_variant	28/29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.5125A>G	p.Thr1709Ala	missense_variant	28/29	5	NM_153700.2	ENSP00000401513	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 27 AN: 151264 Hom.: 0 Cov.: 22 FAILED QC

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00137

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000541 AC: 79 AN: 1460532 Hom.: 6 Cov.: 32 AF XY: 0.0000647 AC XY: 47 AN XY: 726562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000330

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000178 AC: 27 AN: 151382 Hom.: 0 Cov.: 22 AF XY: 0.000216 AC XY: 16 AN XY: 73962

Gnomad4 AFR AF: 0.000170

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00137

Gnomad4 SAS AF: 0.00126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000288 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 21, 2022

PM2_supporting, PM3 -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2023

The p.Thr1709Ala variant in STRC has been reported in 4 individuals with hearing loss, all of whom carried a second pathogenic STRC variant (Vona 2015, Kim 2016, Baux 2017, LMM data). It has also been identified in 0.06% (12/19778) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3. (This variant did not meet the variant calling quality criteria, and was included because it has been previously reported as a clinically significant variant.) -

STRC-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2024

The STRC c.5125A>G variant is predicted to result in the amino acid substitution p.Thr1709Ala. This variant has been reported along with another potentially pathogenic variant in three patients with hearing loss. Although two of these studies confirmed the location of this variant in the STRC functional gene, further evidence of pathogenicity was not presented (Vona et al. 2015. PubMed ID: 26011646; Kim et al. 2016. PubMed ID: 27057829; Kim et al. 2020. PubMed ID: 32203226; Baux et al. 2017. PubMed ID: 29196752). This variant in exon 28 corresponds to a known STRCP1 pseudogene variant, and therefore presence of this variant in the functional gene (as in this patient) may be indicative of a large deletion or gene conversion event on the same allele. While we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.17	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.50	N;N
REVEL	Uncertain	0.64
Sift	Benign	0.17	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;P
Vest4		0.43
MutPred		0.29		Loss of loop (P = 0.1242);.;
MVP		0.78
ClinPred		0.16	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1336307815; hg19: chr15-43892272; COSMIC: COSV55853435; COSMIC: COSV55853435;