rs587776446

Variant names:

• chr10-122506767-C-T
• rs587776446
• NM_002775.5:c.854C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_002775.5(HTRA1):​c.854C>T​(p.Pro285Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 7.75
• Publications: 20 publications found

Genes affected

HTRA1 (HGNC:9476): (HtrA serine peptidase 1) This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]

HTRA1 Gene-Disease associations (from GenCC):

• CARASIL syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• genetic cerebral small vessel disease

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• HTRA1-related autosomal dominant cerebral small vessel disease

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002775.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 10-122506767-C-T is Pathogenic according to our data. Variant chr10-122506767-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 156100.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.854C>T	p.Pro285Leu	missense_variant	Exon 4 of 9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.854C>T	p.Pro285Leu	missense_variant	Exon 4 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.536C>T	p.Pro179Leu	missense_variant	Exon 4 of 9			ENSP00000498033.1
HTRA1	ENST00000420892.1	c.77C>T	p.Pro26Leu	missense_variant	Exon 1 of 6	2		ENSP00000412676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251248 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461656 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the HTRA1 protein (p.Pro285Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of HTRA1-related conditions (PMID: 23963851, 27164673, 27353043, 36253578; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156100). 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 expected to disrupt HTRA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HTRA1 function (PMID: 27164673). This variant disrupts the p.Pro285 amino acid residue in HTRA1. Other variant(s) that disrupt this residue have been observed in individuals with HTRA1-related conditions (PMID: 26063658), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CARASIL syndrome Uncertain:1 Other:1

Sep 18, 2015

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

CARASIL syndrome;C4225211:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 Pathogenic:1

May 15, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HTRA1 c.854C>T (p.Pro285Leu) variant has been reported in at least eight individuals affected with autosomal dominant HTRA1-related cerebral small vessel disease and is reported to segregate with the disease in five individuals in one family (Chen Y et al., PMID: 23963851; Fokstuen S et al., PMID: 27353043; He Z et al., PMID: 36253578; Nozaki H et al., PMID: 27164673; Uemura M et al., PMID: 36261288; Wu C et al., PMID: 36380532; Zhang C et al., PMID: 36047879). This variant has also been reported in the literature in the homozygous state in an individual affected with HTRA1-related cerebral small vessel disease, whose parents were heterozygous for the variant. The father reportedly had moderate symptoms, including multiple lacunar infarcts and diffuse leukoencephalopathy (Chen Y et al., PMID: 23963851). This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters and as a likely pathogenic variant by one submitter. It is observed in only 1/251,248 alleles in the general population (gnomAD v.2.1.1), indicating that it is not a common variant. Computational predictors indicate that the variant is damaging, providing evidence consistent with an impact on HTRA1 function. Functional studies show decreased protease activity, indicating that this variant affects protein function (Nozaki H et al., PMID: 27164673).Another variant in the same codon, c.854C>A (p.Pro285Gln), has been reported in a 50-year-old male with transient ischemic attack, gait disturbance, white matter hyperintensities, and status cribrosum, with additional functional testing supporting pathogenicity (Verdura E et al., PMID: 26063658; ClinVar). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 Pathogenic:1

Nov 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 1 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic/pathogenic by multiple clinical testing laboratories, and as a VUS by one clinical laboratory (ClinVar). It has been reported in a heterozygous state in at least five unrelated individuals with cerebral small vessel disease (PMIDs: 36261288, 36253578, 36035189, 27164673). In addition, this variant has been reported in a homozygous state in an individual with CARASIL, and a heterozygous state in her father with multiple lacunar infarcts and leukoencephalopathy (PMID: 23963851); This variant has limited evidence for segregation with disease. This variant has been reported in a heterozygous state in five affected individuals from a multi-generational family with multiple lacunar infarcts (PMID: 36253578); Missense variant consistently predicted to be damaging by in silico tool or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from proline to leucine; This variant is heterozygous; This gene is associated with both recessive and dominant disease. There is no clear correlation between genotype and mode of inheritance, with several variants reported to cause both forms of disease (PMIDs: 31316458, 32719647); Dominant negative and loss of function are known mechanisms of disease in this gene, and are associated with CARASIL syndrome (MIM#600142) as well as cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, type 2 (MIM#616779) (PMIDs: 29895533, 19387015); Inheritance information for this variant is not currently available in this individual.

HTRA1-related cerebral small vessel disease Pathogenic:1

Oct 25, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HTRA1 c.854C>T (p.Pro285Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251248 control chromosomes (gnomAD). c.854C>T has been reported in the literature in the homozygous state in an individual affected with HTRA1-Related Cerebral Small Vessel Disease, with a brother who was similarly affected but was not available for genetic testing, and whose parents were heterozygous for the variant, the father reportedly having moderate symptoms (Chen_2013). The variant has also been reported in the heterozygous state in multiple individuals with a clinical diagnosis and/or features of HTRA1-Related Cerebral Small Vessel Disease, primarily with an adult onset of over 45 years of age (e.g. Nozaki_2016, Fokstuen_2016, Zhang_2022, Uemura_2023, He_2023). In one report the variant was found in several family members, including two siblings who both both presented with more severe symptoms such as gait disturbances, with white matter hyperintensities and lacunar infarcts at the ages of 59 and 64, whereas of the three younger relatives with the variant, one had alopecia and memory loss at age 30 and the other two (aged 28 and 14) did not manifest symptoms (He_2023). Altogether, these data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Nozaki_2016, Zhang_2022). The most pronounced variant effect results in 10%-<30% protease activity compared to the wild type protein. The following publications have been ascertained in the context of this evaluation (PMID: 23963851, 27353043, 36253578, 27164673, 36261288, 36047879, 36380532). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0	.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	.;H;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.0	.;D;D
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Vest4		0.0
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		0.052	Neutral
Varity_R		0.99
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587776446; hg19: chr10-124266283;