NM_000103.4(CYP19A1):c.1094G>A (p.Arg365Gln) AND Aromatase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 29, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000019399.28

Allele description [Variation Report for NM_000103.4(CYP19A1):c.1094G>A (p.Arg365Gln)]

NM_000103.4(CYP19A1):c.1094G>A (p.Arg365Gln)

Genes:

MIR4713HG:MIR4713 host gene [Gene - HGNC]
CYP19A1:cytochrome P450 family 19 subfamily A member 1 [Gene - OMIM - HGNC]
PIRC66:piwi-interacting RNA cluster 66 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.2

Genomic location:

Preferred name:

NM_000103.4(CYP19A1):c.1094G>A (p.Arg365Gln)

HGVS:

NC_000015.10:g.51212489C>T
NG_007982.1:g.131110G>A
NM_000103.4:c.1094G>AMANE SELECT
NM_001347248.1:c.1094G>A
NM_001347249.2:c.1094G>A
NM_001347250.2:c.1094G>A
NM_001347251.2:c.1094G>A
NM_001347252.2:c.1094G>A
NM_001347253.2:c.1094G>A
NM_001347254.2:c.1094G>A
NM_001347255.2:c.1094G>A
NM_001347256.2:c.1094G>A
NM_031226.3:c.1094G>A
NP_000094.2:p.Arg365Gln
NP_001334177.1:p.Arg365Gln
NP_001334178.1:p.Arg365Gln
NP_001334179.1:p.Arg365Gln
NP_001334180.1:p.Arg365Gln
NP_001334181.1:p.Arg365Gln
NP_001334182.1:p.Arg365Gln
NP_001334183.1:p.Arg365Gln
NP_001334184.1:p.Arg365Gln
NP_001334185.1:p.Arg365Gln
NP_112503.1:p.Arg365Gln
NC_000015.9:g.51504686C>T
P11511:p.Arg365Gln

Protein change:

R365Q; ARG365GLN

Links:

UniProtKB: P11511#VAR_016962; OMIM: 107910.0007; dbSNP: rs80051519

NCBI 1000 Genomes Browser:

rs80051519

Molecular consequence:

NM_000103.4:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347248.1:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347249.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347250.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347251.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347252.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347253.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347254.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347255.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347256.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_031226.3:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Aromatase deficiency
Synonyms:: Increased aromatase activity; Pseudohermaphroditism, female, due to placental aromatase deficiency
Identifiers:: MONDO: MONDO:0013301; MedGen: C1960539; Orphanet: 91; OMIM: 613546

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039689	OMIM	no assertion criteria provided	Pathogenic (Jul 10, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003807717	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000039689

OMIM

no assertion criteria provided

Pathogenic
(Jul 10, 1997)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV003807717

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 29, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Effect of testosterone and estradiol in a man with aromatase deficiency.

Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER.

N Engl J Med. 1997 Jul 10;337(2):91-5. No abstract available.

PubMed [citation]

PMID:: 9211678

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000039689.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a man with aromatase deficiency (613546) whose parents were first cousins, Carani et al. (1997) identified a G-to-A transition at nucleotide 1094 in exon 9 of the P-450 aromatase gene, resulting in a glutamine instead of an arginine at codon 365. The mutation abolished a site cleaved by the restriction enzyme Acc651; restriction analysis showed that both parents were heterozygous for the mutation. Expression studies in COS-1 cells showed that the aromatase activity of the mutant protein was 0.4% of that of the wildtype protein in the presence of the same amount of total cellular protein. At 18 years of age the patient was 170 cm tall and he continued to grow, reaching a height of 187 cm at the age of 31 and 190 cm at the age of 38. Androgen therapy was ineffective; estrogen therapy resulted in increased spinal bone mineral density and complete epiphyseal closure after 9 months. The increases in bone mineral density, serum levels of alkaline phosphatase and osteocalcin, and urinary excretion of pyridinoline were similar to those that occurred during normal skeletal maturation during puberty. Thus, the authors proposed that eunuchoid skeletal features may result mainly from a deficiency of estrogen, rather than a deficiency of androgen. The lack of eunuchoid skeletal development in patients with complete androgen insensitivity supported this view. Skeletal pain, especially in the knees, was a clinical feature. At age 31 years his arm span was 204 cm and the ratio of upper segment to lower segment was 0.85. He showed bilateral genu valgum. There was no gynecomastia and penis size and pattern of pubic hair were normal. Psychosexual orientation was heterosexual and his libido and erections were normal.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807717.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP3 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Mar 11, 2023

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