10-54369194-G-C

Position:

• chr10-54369194-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001384140.1(PCDH15):​c.400C>G​(p.Arg134Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.25

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-54369193-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 10-54369194-G-C is Pathogenic according to our data. Variant chr10-54369194-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54369194-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.400C>G	p.Arg134Gly	missense_variant	5/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.400C>G	p.Arg134Gly	missense_variant	5/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.400C>G	p.Arg134Gly	missense_variant	5/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.400C>G	p.Arg134Gly	missense_variant	5/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2003	- -
Likely pathogenic, flagged submission	clinical testing	Baylor Genetics	Mar 11, 2023	- -

Usher syndrome type 1F Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 19, 2023

Variant summary: PCDH15 c.400C>G (p.Arg134Gly) results in a non-conservative amino acid change located in the Cadherin-like (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250744 control chromosomes. c.400C>G has been reported in the literature in multiple individuals affected with nonsyndromic hearing loss DFNB23 or Usher Syndrome Type 1F (examples: Ahmed_2008, Kletke_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18719945, 27743452). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 15, 2013

The Arg134Gly variant in PCDH15 has been previously identified in 2 unrelated Pa kistani individuals with nonsyndromic hearing loss, both of whom were homozygous , and was absent in 500 ethnically matched chromosomes (Ahmed 2003, Ahmed 2008). In addition, the variant segregated in 4 affected family members, and all affec ted individuals were reported to have hearing loss and normal electroretinograms (Ahmed 2003, Ahmed 2008). Computational analyses (biochemical amino acid proper ties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong suppor t for or against an impact to the protein. In summary, this variant is likely to be pathogenic, though additional familial or functional studies are required to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.0	.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.10	T;.;.;.;.;.;D;D;.;D;.;T;T;.;D;.;.;D;D;T;.;D;D;D
Sift4G	Uncertain	0.0030	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.87
MutPred		0.81		Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);.;Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);.;Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);.;Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);.;Loss of MoRF binding (P = 0.0189);.;Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);.;.;Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);Loss of MoRF binding (P = 0.0189);
MVP		0.82
MPC		0.23
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.37
gMVP		0.67

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: rs137853003; hg19: chr10-56128954;