rs61754365

Positions:

• chr11-89178603-G-A
• chr11-89178603-G-C
• chr11-89178603-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_000372.5(TYR):​c.650G>A​(p.Arg217Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,612,568 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. R217W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 1.29

Genes affected

TYR (HGNC:12442): (tyrosinase) The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000372.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-89178602-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 99573.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 11-89178603-G-A is Pathogenic according to our data. Variant chr11-89178603-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89178603-G-A is described in Lovd as [Pathogenic]. Variant chr11-89178603-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-89178603-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3665866). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYR	NM_000372.5	c.650G>A	p.Arg217Gln	missense_variant	1/5	ENST00000263321.6
TYR	XM_011542970.3	c.650G>A	p.Arg217Gln	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYR	ENST00000263321.6	c.650G>A	p.Arg217Gln	missense_variant	1/5	1	NM_000372.5	P1
TYR	ENST00000526139.1	n.711G>A		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 250834 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000649

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000202 AC: 295 AN: 1460492 Hom.: 1 Cov.: 33 AF XY: 0.000211 AC XY: 153 AN XY: 726444

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.000537

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000730

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74272

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 16, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.039%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099575). The variant has been reported with a pathogenic variant as either compound heterozygous or homozygous in multiple similarly affected unrelated individuals (PMID: 18463683 , 27734839). A different missense change at the same codon (p.Arg217Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003795). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TYR: PM3:Very Strong, PM1, PM2, PM5, PP4 -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 217 of the TYR protein (p.Arg217Gln). This variant is present in population databases (rs61754365, gnomAD 0.06%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 10987646, 28976636, 29345414). 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: 99575). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TYR protein function with a negative predictive value of 80%. This variant disrupts the p.Arg217 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1642278, 10987646, 27734839, 28266639). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34897530, 32966289, 8477259, 13680365, 19208379, 28976636, 28451379, 18463683, 31233279, 16170149, 19060277, 28629449, 31980526, 33050356, 34426522, 31589614) -

Oculocutaneous albinism Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The TYR c.650G>A (p.Arg217Gln) missense variant has been reported in at least three studies and is found in a compound heterozygous state in at least five individuals with oculocutaneous albinism, with at least one individual carrying a pathogenic variant in trans (Wang et al. 2005; Hutton and Spritz 2008; Grønskov et al. 2009). The variant was not found in 50 healthy unrelated control individuals (Grønskov et al. 2009) and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Two additional variants in the Arg217 residue (p.Arg217Trp and p.Arg217Gly) have been reported in individuals with oculocutaneous albinism in a compound heterozygous state (Hutton and Spritz 2008). Based on the evidence, the p.Arg217Gln variant is classified as likely pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.0091	T
MutationAssessor	Benign	-0.015	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.25	N
REVEL	Uncertain	0.55
Sift	Benign	0.45	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.67
MVP		0.88
MPC		0.011
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.058
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61754365; hg19: chr11-88911771;